1
|
Li J, Guo C, Yang X, Xie W, Mi W, Hua C, Tang C, Wang H. Effects of natural products on macrophage immunometabolism: A new frontier in the treatment of metabolic diseases. Pharmacol Res 2025; 213:107634. [PMID: 39889866 DOI: 10.1016/j.phrs.2025.107634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/20/2025] [Accepted: 01/27/2025] [Indexed: 02/03/2025]
Abstract
Immunometabolic variations in macrophages critically influence their differentiation into pro-inflammatory or anti-inflammatory phenotypes, thereby contributing to immune homeostasis, defense against infection, and tissue repair. Dysregulation of macrophage immunometabolism has been closely implicated in several metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), hypertension, atherosclerosis, and gout, which positions macrophages as potential therapeutic targets. Recently, several natural products that target macrophage metabolic pathways have shown significant efficacy in managing metabolic diseases; however, a systematic review of these findings has yet to be conducted. This study consolidates natural products with immunoregulatory properties, including flavonoids, phenols, terpenoids, and naphthoquinones, which can alleviate chronic inflammation associated with metabolic disorders by modulating macrophage metabolic pathways, such as aerobic glycolysis, oxidative phosphorylation (OXPHOS), and fatty acid oxidation (FAO). This review aims to elucidate the metabolic regulation of the immune system, analyze metabolic alterations in macrophage associated with metabolic diseases, and summarize the beneficial roles of natural products in immunometabolism, providing novel insights for the prevention and therapeutic management of metabolic diseases.
Collapse
Affiliation(s)
- Jiani Li
- Beijing Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Chen Guo
- Beijing Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xiaofei Yang
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Weinan Xie
- Beijing University of Chinese Medicine, Beijing 100029, China
| | - Wenjing Mi
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Chenglong Hua
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Tang
- Beijing Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Han Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
| |
Collapse
|
2
|
Souza M, Amaral MJM, Lima LCV, Villela-Nogueira CA. Meta-Analysis of Placebo-Treated Patients: Dropout Rates From Treatment in MASH Randomised Controlled Trials. Aliment Pharmacol Ther 2025. [PMID: 39807647 DOI: 10.1111/apt.18498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/22/2024] [Accepted: 01/04/2025] [Indexed: 01/16/2025]
Abstract
BACKGROUND Dropout is common and affects the statistical power and randomization balance of randomised controlled trials (RCTs). AIMS To estimate the dropout rate in RCTs of metabolic dysfunction-associated steatohepatitis (MASH) and to examine factors associated with dropout in placebo-treated participants. METHODS PubMed and Cochrane databases were searched for phase 2-4 MASH RCTs with placebo arms through November 24, 2024. Dropout was defined as the attrition of patients included in the intention-to-treat analysis but did not complete treatment. RCTs were qualitatively reviewed to assess the expected and observed dropouts. Generalised linear mixed model was used to estimate pooled dropout rates. RESULTS Sixty RCTs with 3230 placebo-treated participants with MASH were analysed. Thirty-three RCTs reported the dropout rate used to estimate the effect size. Of these, 60.6%, 36.4%, and 3.0% had an expected dropout rate that was higher, lower, and similar, respectively, than the observed dropout rate in the placebo arm. Overall, the dropout rate was 11.06% (95% confidence interval [CI] 9.07 to 13.42), with a higher rate in phase 3-4 trials than in phase 2 trials. The corresponding rates due to adverse events, loss to follow-up and patient choice were 2.41% (95% CI 1.67 to 3.48), 1.79% (95% CI 1.06 to 2.99) and 4.06% (95% CI 2.97 to 5.53), respectively. Meta-regression determined that the dropout rate increased with longer treatment duration. CONCLUSION Placebo dropout in MASH RCTs is significant, mainly due to patient choice. Factors such as trial phase and treatment duration should be considered when calculating sample size in future clinical trials.
Collapse
Affiliation(s)
- Matheus Souza
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcio J M Amaral
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luan C V Lima
- Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | |
Collapse
|
3
|
Jin Y, Xing J, Dai C, Jin L, Zhang W, Tao Q, Hou M, Li Z, Yang W, Feng Q, Wang H, Yu Q. NK cell exhaustion in Wilson's disease revealed by single-cell RNA sequencing predicts the prognosis of cholecystitis. eLife 2024; 13:RP98867. [PMID: 39854622 PMCID: PMC11684787 DOI: 10.7554/elife.98867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2025] Open
Abstract
Metabolic abnormalities associated with liver disease have a significant impact on the risk and prognosis of cholecystitis. However, the underlying mechanism remains to be elucidated. Here, we investigated this issue using Wilson's disease (WD) as a model, which is a genetic disorder characterized by impaired mitochondrial function and copper metabolism. Our retrospective clinical study found that WD patients have a significantly higher incidence of cholecystitis and a poorer prognosis. The hepatic immune cell landscape using single-cell RNA sequencing showed that the tissue immune microenvironment is altered in WD, mainly a major change in the constitution and function of the innate immune system. Exhaustion of natural killer (NK) cells is the fundamental factor, supported by the upregulated expression of inhibitory receptors and the downregulated expression of cytotoxic molecules, which was verified in clinical samples. Further bioinformatic analysis confirmed a positive correlation between NK cell exhaustion and poor prognosis in cholecystitis and other inflammatory diseases. The study demonstrated dysfunction of liver immune cells triggered by specific metabolic abnormalities in WD, with a focus on the correlation between NK cell exhaustion and poor healing of cholecystitis, providing new insights into the improvement of inflammatory diseases by assessing immune cell function.
Collapse
Affiliation(s)
- Yong Jin
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jiayu Xing
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Chenyu Dai
- Department of Cadre Cardiology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Lei Jin
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, China
| | - Wanying Zhang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Qianqian Tao
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, China
| | - Mei Hou
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Ziyi Li
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Institute of Chinese Medicine Surgery, Anhui Academy of Chinese Medicine, Hefei, China
| | - Wen Yang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Qiyu Feng
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Hongyang Wang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
- National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Qingsheng Yu
- Department of Cadre Cardiology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- Department of General Surgery, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| |
Collapse
|
4
|
Saberian A, Dehghan A, Homayounfar R, Kaffashan S, Zarei F, Niknejad S, Farjam M. Determining the sensitivity and specificity of the calculated fatty liver index in comparison with ultrasound. BMC Gastroenterol 2024; 24:443. [PMID: 39623301 PMCID: PMC11610269 DOI: 10.1186/s12876-024-03535-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease in human history and it is expected to surpass other causes of liver disease mortality by 2030. Therefore, finding an alternative way to diagnose steatosis in the early stage when imaging modalities are not available is crucial. This study decided to validate the optimal cut-off points and the sensitivity and specificity of the Fatty Liver Index (FLI) based on the Iranian population compared to ultrasonography. METHODS The data of 367 individuals, 108 males and 259 females over 35, were analyzed. Hepatic steatosis was identified by ultrasound. FLI was determined from waist circumference, gamma-glutamyl transferase, triglyceride, and body mass index data. The receiver operating characteristic curve (ROC) was used to determine the best FLI index cut point for diagnosing nonalcoholic fatty liver. The sensitivity and specificity indices were calculated for the determined cut point. RESULTS The AUC of the FLI index in diagnosing NAFLD in the total population was 0.733 (95% CI: 0.68-0.77, specificity = 0.6705, sensitivity = 0.7320) with the optimal COP of 40.6. There was a statistically significant association between non-alcoholic liver disease and FLI-based ultrasound (p < 0.0001). Furthermore, the sex-specific optimal COPs of FLI was 33.4, specificity = 0.6071, sensitivity = 0.8462 in men vs. 27.8, sensitivity = 0.8233, specificity = 0.7655 in women. CONCLUSION FLI is a reliable tool for identifying individuals with NAFLD. It has the potential to aid in detecting and managing this condition in large-scale populations while other methods are not available. We also determine an optimal COP of 40.6 with sensitivity and specificity of 73.20% and 67.05% in the general population, respectively.
Collapse
Affiliation(s)
- Arash Saberian
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Azizallah Dehghan
- Department of Epidemiology, Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Reza Homayounfar
- National Nutrition and Food Technology Research Institute, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeid Kaffashan
- Department of Radiology, School of Medicine, Fasa University of Medical Science, Fasa, Iran
| | - Fariba Zarei
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sepideh Niknejad
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, 7156685691, Iran.
| | - Mojtaba Farjam
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, 74616-86688, Iran.
| |
Collapse
|
5
|
Park Y, Jung J, Han S, Kim G. Metabolic dysfunction-associated steatotic liver disease and MetALD increases the risk of liver cancer and gastrointestinal cancer: A nationwide cohort study. Aliment Pharmacol Ther 2024; 60:1599-1608. [PMID: 39304991 PMCID: PMC11599781 DOI: 10.1111/apt.18286] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/13/2024] [Accepted: 09/09/2024] [Indexed: 11/28/2024]
Abstract
BACKGROUND The new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) substituting nonalcoholic fatty liver disease was proposed along with a new category of MASLD with increased alcohol intake (MetALD). AIMS We aimed to explore the cancer risk by MASLD and MetALD. METHODS This nationwide cohort study included 3,596,709 participants who underwent a health check-up in 2011 in South Korea. Steatotic liver disease (SLD) was defined as a fatty liver index ≥30. Participants were categorized into four exclusive groups: MASLD, MetALD, other combination aetiology and no SLD. The subdistribution hazard ratio (SHR) was calculated using the Fine-Gray model after adjusting other variables. RESULTS During the 33.9 million person-years of follow-up, 285,845 participants (7.9%) developed cancers. Compared with no SLD, MASLD, MetALD and other combination aetiology had an increased risk of all cancer. Liver cancer risk escalated from no SLD to MASLD (SHR, 1.16; 95% CI, 1.12-1.21), MetALD (SHR, 2.06; 95% CI, 1.92-2.20) and other combination aetiology (SHR, 8.16; 95% CI, 7.69-8.67). Gastrointestinal cancers including oesophagus, stomach, colorectal, biliary and pancreas cancers increased in MASLD (SHR, 1.13; 95% CI, 1.11-1.15), MetALD (SHR, 1.17; 95% CI, 1.14-1.21) and other combination aetiology (SHR, 1.09; 95% CI, 1.05-1.13). A modest increase in lung cancer and hormone-sensitive cancer was observed with MASLD. CONCLUSIONS This study showed that MASLD and MetALD are associated with an increased risk of cancer, particularly liver and gastrointestinal cancers. The findings build new evidence for the clinical outcomes of MetALD while highlighting the importance of managing alcohol intake properly in MASLD and MetALD.
Collapse
Affiliation(s)
- Yewan Park
- Department of Internal Medicine, College of Medicine, Kyung Hee University HospitalKyung Hee UniversitySeoulRepublic of Korea
| | - Jooyi Jung
- Department of BiostatisticsKorea UniversitySeoulRepublic of Korea
| | - Seungbong Han
- Department of BiostatisticsKorea UniversitySeoulRepublic of Korea
| | - Gi‐Ae Kim
- Department of Internal Medicine, College of Medicine, Kyung Hee University HospitalKyung Hee UniversitySeoulRepublic of Korea
| |
Collapse
|
6
|
Kwan SH, Esteves F, Davis E, Gonzalez de Mejia E. Chemical characterization and DPP IV inhibitory capacity of purified adzuki bean β-vignin digest in comparison to soybean β-conglycinin and in vitro effect of β-vignin on diabetic-related outcomes. Food Chem 2024; 467:142285. [PMID: 39644661 DOI: 10.1016/j.foodchem.2024.142285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 11/10/2024] [Accepted: 11/27/2024] [Indexed: 12/09/2024]
Abstract
Adzuki bean (AB) is a legume with a low glycemic index and is traditionally used in Asian cultures to modulate type 2 diabetes (T2D). Our objectives were to characterize the functional peptides from purified AB β-vignin after simulated gastrointestinal digestion in comparison to soybean β-conglycinin, to evaluate their DPP IV inhibitory capacity, and to determine in vitro the effect of digested AB β-vignin on diabetic-related outcomes using HepG2 cells in healthy and insulin-resistant states. Five peptides (215-742 Da) from AB β-vignin and five peptides (215-447 Da) from β-conglycinin were identified to exhibit bioactivity as DPP IV inhibitors. Molecular docking demonstrated peptides could bind to DPP IV at the same binding site as a diabetic medication, linagliptin. Digested AB β-vignin significantly increased (p < 0.05) hepatic glucose uptake (> 290 %) via DPP IV inhibition (> 40 %) in healthy and insulin-resistant states. IRS-1, Akt-1, and Glut 2 increased after treating cells with digested AB β-vignin in healthy and insulin-resistant states.
Collapse
Affiliation(s)
- Shu Hang Kwan
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA
| | - Frida Esteves
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA; Tecnologico de Monterrey, Monterrey, Mexico
| | - Emily Davis
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA
| | - Elvira Gonzalez de Mejia
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA; Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA.
| |
Collapse
|
7
|
Ling S, Diao H, Lu G, Shi L. Associations between serum levels of liver function biomarkers and all-cause and cause-specific mortality: a prospective cohort study. BMC Public Health 2024; 24:3302. [PMID: 39604890 PMCID: PMC11600561 DOI: 10.1186/s12889-024-20773-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 11/15/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND The liver plays critical roles in human health. Circulating level of liver function biomarkers may associate with the long-term and short-term mortality in general population. METHODS We used data from US National Health and Nutrition Examination Survey 1988-94 and 1999-2014. People aged ≥ 20 years with measured serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), total bilirubin (TB), and albumin (ALB) at baseline were included. All-cause and cause-specific mortality was identified from the National Death Index through 31 December 2015. Additive Cox regression models were applied to assess the correlation patterns between the serum level of these analytes and mortality risk. RESULTS A total of 44,508 participants were included; among them, 9,721 deaths occurred during a mean follow-up of 12.5 years. A "J-shaped" correlation was found between serum levels of ALT, AST, and TB and all-cause mortality. The risk of mortality monotonically increased with increasing GGT and ALP levels when their levels exceeded the valley points. A "L-shaped" correlation was found between the serum level of ALB and all-cause mortality. The correlation patterns were comparable among deaths from different causes and were consistent in subgroup and sensitivity analyses. While the integration of all six liver function biomarkers did not yield an optimal predictive performance for mortality (area under ROC curve = 0.706), it demonstrated a significantly better performance compared to any single biomarker.. CONCLUSION Circulating liver function biomarkers showed diverse nonlinear correlations with mortality and may be utilized as part of a screening process to help identify individuals who may be at elevated risk of mortality.
Collapse
Affiliation(s)
- Shunhu Ling
- Department of Internal Medicine, Hanshan People's Hospital in Anhui Province, Ma'anshan, 238101, Anhui Province, China
| | - Haiping Diao
- Department of Proctology, Hanshan Hospital of Traditional Chinese Medicine in Anhui Province, Ma'anshan, 238101, Anhui Province, China
| | - Guangbing Lu
- Department of Respiration, Meishan Hospital of Traditional Chinese Medicine in Sichuan Province, Meishan, 620010, Sichuan Province, China
| | - Luhua Shi
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| |
Collapse
|
8
|
Stroes ASR, Vos M, Benninga MA, Koot BGP. Pediatric MASLD: current understanding and practical approach. Eur J Pediatr 2024; 184:29. [PMID: 39560782 DOI: 10.1007/s00431-024-05848-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/20/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most prevalent chronic liver disease in children in industrialized countries mainly due to the rise in obesity and overweight. Besides risk of progressive liver damage, MASLD also carries an increased risk of extra-hepatic morbidity, most importantly type 2 diabetes mellitus and cardiovascular disease. Important challenges remain in the prevention, detection, and treatment of this prevalent disorder. This review outlines the epidemiology and risk factors of MASLD and provides an approach to screening, diagnosis, and treatment based on current best available evidence and expert opinion. What is known: • NAFLD/MASLD is a common disorder in children strongly related to obesity/overweight and insulin resistance. • This silent disorder is underdiagnosed due to lack of awareness and lack of simple diagnostic criteria. What is new: • New diagnostic criteria have transformed NAFLD/MASLD from a diagnosis of exclusion to a positive diagnosis with simple criteria. • Effective treatments are emerging for adults and will likely become available for children. • Identifying children with NAFLD/MASLD has become even more important due to this new treatment perspective.
Collapse
Affiliation(s)
- Anne-Sophie R Stroes
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Miriam Vos
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine & Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Marc A Benninga
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Bart G P Koot
- Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
| |
Collapse
|
9
|
Motamed Shariati M, Khazaei S, Yaghoobi M. Choroidal vascularity index in health and systemic diseases: a systematic review. Int J Retina Vitreous 2024; 10:87. [PMID: 39558436 PMCID: PMC11575059 DOI: 10.1186/s40942-024-00607-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 11/06/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND The choroid, a highly vascular structure within the eye, is significantly influenced by various systemic conditions. The advent of enhanced depth optical coherence tomography has improved our ability to evaluate choroidal pathophysiology. The choroidal vascularity index (CVI), a noninvasive and reliable tool, serves as an effective means of assessing the choroidal vascular structure. Recent studies have increasingly focused on exploring CVI alterations under different systemic conditions. This study aims to provide a comprehensive summary of the latest research findings in this area. METHODS A systematic literature review was conducted on October 1, 2023, using two databases, MEDLINE (via PubMed) and Scopus. Search terms were tailored specifically for each database to ensure a thorough exploration of relevant literature. The studies identified were qualitatively assessed, with particular emphasis on outcomes related to CVI and choroidal thickness. RESULTS A total of 48 studies were included in the review, encompassing a diverse range of systemic conditions such as diabetes, central nervous system disorders, cardiovascular diseases, autoimmune disorders, and infectious diseases. Notable reductions in CVI were observed in diabetic retinopathy, autoimmune diseases, and neurodegenerative disorders. Additionally, the review highlighted variations in CVI values related to the severity of systemic diseases, indicating its potential use as a biomarker for disease progression. CONCLUSION This review highlights the significant correlation between variations in the choroidal vascularity index and diverse systemic conditions affecting hemodynamics. An enhanced understanding of CVI provides deeper insights into the pathophysiological mechanisms underlying these disorders and positions CVI as a promising biomarker for early detection and monitoring. Nevertheless, its clinical utility warrants careful assessment. Future research should address the potential limitations of CVI to fully capitalize on its diagnostic and prognostic potential.
Collapse
Affiliation(s)
- Mehrdad Motamed Shariati
- Eye Research Center, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran
| | - Sahel Khazaei
- Eye Research Center, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran.
| | - Mariye Yaghoobi
- Eye Research Center, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran
| |
Collapse
|
10
|
Pagano S, Somm E, Juillard C, Liaudet N, Ino F, Ferrari J, Braunersreuther V, Jornayvaz FR, Vuilleumier N. Linking Antibodies Against Apolipoprotein A-1 to Metabolic Dysfunction-Associated Steatohepatitis in Mice. Int J Mol Sci 2024; 25:11875. [PMID: 39595946 PMCID: PMC11594174 DOI: 10.3390/ijms252211875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/29/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MASLD) is a common liver and health issue associated with heightened cardiovascular disease (CVD) risk, with Cytokeratin 18 (CK-18) as a marker of liver injury across the MASLD to cirrhosis spectrum. Autoantibodies against apolipoprotein A-1 (AAA-1s) predict increased CVD risk, promoting atherosclerosis and liver steatosis in apoE-/- mice, though their impact on liver inflammation and fibrosis remains unclear. This study examined AAA-1s' impact on low-grade inflammation, liver steatosis, and fibrosis using a MASLD mouse model exposed to AAA-1s passive immunization (PI). Ten-week-old male C57BL/6J mice under a high-fat diet underwent PI with AAA-1s or control antibodies for ten days. Compared to controls, AAA-1-immunized mice showed higher plasma CK-18 (5.3 vs. 2.1 pg/mL, p = 0.031), IL-6 (13 vs. 6.9 pg/mL, p = 0.035), IL-10 (27.3 vs. 9.8 pg/mL, p = 0.007), TNF-α (32.1 vs. 24.2 pg/mL, p = 0.032), and liver steatosis (93.4% vs. 73.8%, p = 0.007). Transcriptomic analyses revealed hepatic upregulation of pro-fibrotic mRNAs in AAA-1-recipient mice, though histological changes were absent. In conclusion, short-term AAA-1 PI exacerbated liver steatosis, inflammation, and pro-fibrotic gene expression, suggesting that AAA-1s may play a role in MASLD progression. Further research with prolonged AAA-1 exposure is warranted to clarify their potential role in liver fibrosis and associated complications.
Collapse
Affiliation(s)
- Sabrina Pagano
- Division of Laboratory Medicine, Diagnostic Department, Geneva University Hospitals, 1211 Geneva, Switzerland;
- Department of Medicine, Medical Faculty, Geneva University, 1211 Geneva, Switzerland;
| | - Emmanuel Somm
- Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Internal Medicine, Geneva University Hospitals, 1211 Geneva, Switzerland; (E.S.); (F.I.); (F.R.J.)
- Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center, the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Catherine Juillard
- Department of Medicine, Medical Faculty, Geneva University, 1211 Geneva, Switzerland;
| | - Nicolas Liaudet
- Bioimaging Core Facility, Medical Faculty, University of Geneva, 1211 Geneva, Switzerland;
| | - Frédérique Ino
- Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Internal Medicine, Geneva University Hospitals, 1211 Geneva, Switzerland; (E.S.); (F.I.); (F.R.J.)
- Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center, the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Johan Ferrari
- Division of Clinical Pathology, Diagnostic Department, Geneva University Hospitals, 1211 Geneva, Switzerland; (J.F.); (V.B.)
| | - Vincent Braunersreuther
- Division of Clinical Pathology, Diagnostic Department, Geneva University Hospitals, 1211 Geneva, Switzerland; (J.F.); (V.B.)
| | - François R. Jornayvaz
- Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Department of Internal Medicine, Geneva University Hospitals, 1211 Geneva, Switzerland; (E.S.); (F.I.); (F.R.J.)
- Department of Cell Physiology and Metabolism, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center, the Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
| | - Nicolas Vuilleumier
- Division of Laboratory Medicine, Diagnostic Department, Geneva University Hospitals, 1211 Geneva, Switzerland;
- Department of Medicine, Medical Faculty, Geneva University, 1211 Geneva, Switzerland;
| |
Collapse
|
11
|
Hosseini Shabanan S, Martins VF, Wolfson T, Weeks JT, Ceriani L, Behling C, Chernyak V, El Kaffas A, Borhani AA, Han A, Wang K, Fowler KJ, Sirlin CB. MASLD: What We Have Learned and Where We Need to Go-A Call to Action. Radiographics 2024; 44:e240048. [PMID: 39418184 PMCID: PMC11580021 DOI: 10.1148/rg.240048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/16/2024] [Accepted: 04/24/2024] [Indexed: 10/19/2024]
Abstract
Since its introduction in 1980, fatty liver disease (now termed metabolic dysfunction-associated steatotic liver disease [MASLD]) has grown in prevalence significantly, paralleling the rise of obesity worldwide. While MASLD has been the subject of extensive research leading to significant progress in the understanding of its pathophysiology and progression factors, several gaps in knowledge remain. In this pictorial review, the authors present the latest insights into MASLD, covering its recent nomenclature change, spectrum of disease, epidemiology, morbidity, and mortality. The authors also discuss current qualitative and quantitative imaging methods for assessing and monitoring MASLD. Last, they propose six unsolved challenges in MASLD assessment, which they term the proliferation, reproducibility, reporting, needle-in-the-haystack, availability, and knowledge problems. These challenges offer opportunities for the radiology community to proactively contribute to their resolution. The authors conclude with a call to action for the entire radiology community to claim a seat at the table, collaborate with other societies, and commit to advancing the development, validation, dissemination, and accessibility of the imaging technologies required to combat the looming health care crisis of MASLD.
Collapse
Affiliation(s)
| | | | - Tanya Wolfson
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Jake T. Weeks
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Lael Ceriani
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Cynthia Behling
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Victoria Chernyak
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Ahmed El Kaffas
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Amir A. Borhani
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Aiguo Han
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Kang Wang
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Kathryn J. Fowler
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| | - Claude B. Sirlin
- From the Department of Radiology, UC San Diego Altman Clinical and
Translational Research Institute Liver Imaging Group, University of California
San Diego, 9452 Medical Center Dr, La Jolla, CA 92037 (S.H.S., V.F.M., T.W.,
J.T.W., L.C., K.J.F., C.B.S.); Pacific Rim Pathology, San Diego, Calif (C.B.);
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
(V.C.); Department of Radiology, Stanford University School of Medicine,
Stanford, Calif (A.E.K.); Department of Radiology, Northwestern University
Feinberg School of Medicine, Chicago, Ill (A.A.B.); Department of Biomedical
Engineering and Mechanics, Virginia Polytechnic Institute and State University,
Blacksburg, Va (A.H.); and Department of Radiology, University of California San
Francisco, Calif (K.W.)
| |
Collapse
|
12
|
Lopez-Pascual A, Russo-Cabrera JS, Ardaiz N, Palmer T, Graham AR, Uriarte I, Gomar C, Ruiz-Guillamon D, Latasa MU, Arechederra M, Fontanellas A, Monte MJ, Marin JJG, Berasain C, Del Rio CL, Fernandez-Barrena MG, Martini PGV, Schultz JR, Berraondo P, Avila MA. Non-mitogenic FGF19 mRNA-based therapy for the treatment of experimental metabolic dysfunction-associated steatotic liver disease (MASLD). Clin Sci (Lond) 2024; 138:1265-1284. [PMID: 39301694 DOI: 10.1042/cs20241137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/16/2024] [Accepted: 09/18/2024] [Indexed: 09/22/2024]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) represents a global health threat. MASH pathophysiology involves hepatic lipid accumulation and progression to severe conditions like cirrhosis and, eventually, hepatocellular carcinoma. Fibroblast growth factor (FGF)-19 has emerged as a key regulator of metabolism, offering potential therapeutic avenues for MASH and associated disorders. We evaluated the therapeutic potential of non-mitogenic (NM)-FGF19 mRNA formulated in liver-targeted lipid nanoparticles (NM-FGF19-mRNAs-LNPs) in C57BL/6NTac male mice with diet-induced obesity and MASH (DIO-MASH: 40% kcal fat, 20% kcal fructose, 2% cholesterol). After feeding this diet for 21 weeks, NM-FGF19-mRNAs-LNPs or control (C-mRNA-LNPs) were administered (0.5 mg/kg, i.v.) weekly for another six weeks, in which diet feeding continued. NM-FGF19-mRNAs-LNPs treatment in DIO-MASH mice resulted in reduced body weight, adipose tissue depots, and serum transaminases, along with improved insulin sensitivity. Histological analyses confirmed the reversal of MASH features, including steatosis reduction without worsening fibrosis. NM-FGF19-mRNAs-LNPs reduced total hepatic bile acids (BAs) and changed liver BA composition, markedly influencing cholesterol homeostasis and metabolic pathways as observed in transcriptomic analyses. Extrahepatic effects included the down-regulation of metabolic dysfunction-associated genes in adipose tissue. This study highlights the potential of NM-FGF19-mRNA-LNPs therapy for MASH, addressing both hepatic and systemic metabolic dysregulation. NM-FGF19-mRNA demonstrates efficacy in reducing liver steatosis, improving metabolic parameters, and modulating BA levels and composition. Given the central role played by BA in dietary fat absorption, this effect of NM-FGF19-mRNA may be mechanistically relevant. Our study underscores the high translational potential of mRNA-based therapies in addressing the multifaceted landscape of MASH and associated metabolic perturbations.
Collapse
Affiliation(s)
- Amaya Lopez-Pascual
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Joan S Russo-Cabrera
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Nuria Ardaiz
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | | | | | - Iker Uriarte
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | - Celia Gomar
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - David Ruiz-Guillamon
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Maria U Latasa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | - Maria Arechederra
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | - Antonio Fontanellas
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | - Maria J Monte
- CIBERehd, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Jose J G Marin
- CIBERehd, Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain
| | - Carmen Berasain
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | | | - Maite G Fernandez-Barrena
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
- CIBERehd, Madrid, Spain
| | | | | | - Pedro Berraondo
- Immunology and Immunotherapy Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERonc, Madrid, Spain
| | - Matias A Avila
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
- CIBERehd, Madrid, Spain
| |
Collapse
|
13
|
Leith D, Lin YY, Brennan P. Metabolic Dysfunction-associated Steatotic Liver Disease and Type 2 Diabetes: A Deadly Synergy. TOUCHREVIEWS IN ENDOCRINOLOGY 2024; 20:5-9. [PMID: 39526052 PMCID: PMC11548366 DOI: 10.17925/ee.2024.20.2.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 01/11/2024] [Indexed: 11/16/2024]
Abstract
Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) are both facets of the metabolic syndrome, associated with obesity and insulin resistance. MASLD, a term that replaces non-alcoholic fatty liver disease (NAFLD), occurs in up to 70% of people with T2D. Not only do T2D and MASLD commonly co-occur, but there is a synergistic, bidirectional relationship between these conditions, meaning that each affects the natural disease course of the other. As such, it is important for those caring for people with T2D to recognize the importance of this co-diagnosis. In this summary, we detail the synergistic relationship between T2D and MASLD, explain the current challenges in recognizing this common co-diagnosis and suggest practical approaches for those caring for people with T2D to improve the diagnosis and treatment of MASLD.
Collapse
Affiliation(s)
- Damien Leith
- Clinical Research Centre, Ninewells Hospital, Dundee, UK
| | - Yeun Yi Lin
- Clinical Research Centre, Ninewells Hospital, Dundee, UK
| | - Paul Brennan
- Clinical Research Centre, Ninewells Hospital, Dundee, UK
| |
Collapse
|
14
|
Abdelhameed F, Kite C, Lagojda L, Dallaway A, Chatha KK, Chaggar SS, Dalamaga M, Kassi E, Kyrou I, Randeva HS. Non-invasive Scores and Serum Biomarkers for Fatty Liver in the Era of Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD): A Comprehensive Review From NAFLD to MAFLD and MASLD. Curr Obes Rep 2024; 13:510-531. [PMID: 38809396 PMCID: PMC11306269 DOI: 10.1007/s13679-024-00574-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2024] [Indexed: 05/30/2024]
Abstract
PURPOSE OF REVIEW The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide, making it the leading cause of liver related morbidity and mortality. Currently, liver biopsy is the gold standard for assessing individuals with steatohepatitis and fibrosis. However, its invasiveness, sampling variability, and impracticality for large-scale screening has driven the search for non-invasive methods for early diagnosis and staging. In this review, we comprehensively summarise the evidence on the diagnostic performance and limitations of existing non-invasive serum biomarkers and scores in the diagnosis and evaluation of steatosis, steatohepatitis, and fibrosis. RECENT FINDINGS Several non-invasive serum biomarkers and scores have been developed over the last decade, although none has successfully been able to replace liver biopsy. The introduction of new NAFLD terminology, namely metabolic dysfunction-associated fatty liver disease (MAFLD) and more recently metabolic dysfunction-associated steatotic liver disease (MASLD), has initiated a debate on the interchangeability of these terminologies. Indeed, there is a need for more research on the variability of the performance of non-invasive serum biomarkers and scores across the diagnostic entities of NAFLD, MAFLD and MASLD. There remains a significant need for finding valid and reliable non-invasive methods for early diagnosis and assessment of steatohepatitis and fibrosis to facilitate prompt risk stratification and management to prevent disease progression and complications. Further exploration of the landscape of MASLD under the newly defined disease subtypes is warranted, with the need for more robust evidence to support the use of commonly used serum scores against the new MASLD criteria and validation of previously developed scores.
Collapse
Affiliation(s)
- Farah Abdelhameed
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Chris Kite
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, WV1 1LY, UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK
- Chester Medical School, University of Chester, Shrewsbury, SY3 8HQ, UK
| | - Lukasz Lagojda
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Clinical Evidence-Based Information Service (CEBIS), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Alexander Dallaway
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- School of Health and Society, Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton, WV1 1LY, UK
| | - Kamaljit Kaur Chatha
- Department of Biochemistry and Immunology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | | | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Propaupedic and Internal Medicine, Endocrine Unit, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK.
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.
- College of Health, Psychology and Social Care, University of Derby, Derby, DE22 1GB, UK.
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855, Athens, Greece.
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing, Coventry University, Coventry, CV1 5FB, UK.
- Institute for Cardiometabolic Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
| |
Collapse
|
15
|
Chen K, Wei L, Yu S, He N, Zhang F. Identification of autophagy-related signatures in nonalcoholic fatty liver disease and correlation with non-parenchymal cells of the liver. Mol Omics 2024; 20:469-482. [PMID: 38982979 DOI: 10.1039/d4mo00060a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/11/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic hepatic disease. The incidence and prevalence of NAFLD have increased greatly in recent years, and there is still a lack of effective drugs. Autophagy plays an important role in promoting liver metabolism and maintaining liver homeostasis, and defects in autophagy levels are considered to be related to the development of NAFLD. However, the molecular mechanisms of autophagy in NAFLD still remain unknown. In this study, we identified 6 autophagy-associated hub genes using gene expression profiles obtained from the GSE48452 and GSE89632 datasets. Biomarkers were screened according to gene significance (GS) and module membership (MM) using weighted gene co-expression network analysis (WGCNA), and the immune infiltration landscape of the liver in NAFLD patients was explored using the CIBERSORT algorithm. Subsequently, we analyzed the relationship between liver non-parenchymal cells and autophagy-related hub genes using scRNA-seq data (GSE129516). Finally, we separated the NAFLD patients into two groups based on 6 hub genes by consensus clustering and screened 10 potential autophagy-related small molecules based on the cMAP database.
Collapse
Affiliation(s)
- Kaiwei Chen
- Department of Infectious Diseases, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266003, China.
| | - Ling Wei
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
| | - Shengnan Yu
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266003, China.
| | - Ningning He
- School of Basic Medicine, Qingdao Medical College, Qingdao University, Qingdao, 266003, China.
| | - Fengjuan Zhang
- Department of Infectious Diseases, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
| |
Collapse
|
16
|
Lionis C, Papadakis S, Anastasaki M, Aligizakis E, Anastasiou F, Francque S, Gergianaki I, Mendive JM, Marketou M, Muris J, Manolakopoulos S, Papatheodoridis G, Samonakis D, Symvoulakis E, Tsiligianni I. Practice Recommendations for the Management of MASLD in Primary Care: Consensus Results. Diseases 2024; 12:180. [PMID: 39195179 DOI: 10.3390/diseases12080180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND Despite its high prevalence and impact on health, metabolic dysfunction-associated steatotic liver disease (MASLD) is inadequately addressed in European primary care (PC), with a large proportion of cases going undiagnosed or diagnosed too late. A multi-country European research consortium led a project to design and evaluate a patient-centered, integrated model for MASLD screening, diagnosis, and linkage to specialty care for European PC settings. Based on the lessons from this project, the latest research evidence, and existing guidelines for the management of MASLD, we sought to develop a set of practice recommendations for screening, referral, and management of MASLD in PC. METHODS The Rand/UCLA modified Delphi panel method, with two rounds, was used to reach consensus on practice recommendations. The international panel consisted of experts from six countries, representing family medicine, gastroenterology, hepatology, cardiology, and public health. Initially, fifteen statements were drafted based on a synthesis of evidence from the literature and earlier findings from our consortium. Prior to the consensus meeting, the statements were rated by the experts in the first round. Then, in a hybrid meeting, the experts discussed findings from round one, adjusted the statements, and reassessed the updated recommendations in a second round. RESULTS In round one, there was already a high level of consensus on 10 out of 15 statements. After round 2, there were fourteen statements with a high degree of agreement (>90%). One statement was not endorsed. The approved recommendations addressed the following practice areas: risk screening and diagnosis, management of MASLD-lifestyle interventions, pharmacological treatment of MASLD/MASH, pharmacological treatment for co-morbidity, integrated care, surgical management, and other referrals to specialists. CONCLUSIONS The final set of 14 recommendations focuses on increasing comprehensive care for MASLD in PC. The recommendations provide practical evidence-based guidance tailored to PC practitioners. We expect that these recommendations will contribute to the ongoing discussion on systematic approaches to tackling MASLD and supporting European PC providers by integrating the latest evidence into practice.
Collapse
Affiliation(s)
- Christos Lionis
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Sophia Papadakis
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Marilena Anastasaki
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | | | - Foteini Anastasiou
- 4th Local Health Team-Municipality Practice and Academic Unit of Heraklion, Crete, 71303 Heraklion, Greece
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, 2650 Edegem, Belgium
| | - Irini Gergianaki
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Juan Manuel Mendive
- La Mina Primary Health Care Centre, IDIAP Jordi Gol, 08003 Barcelona, Spain
- European Society for Primary Care Gastroenterology, London E1 6HU, UK
| | - Maria Marketou
- Clinic of Cardiology, University Hospital of Heraklion, Crete, 70013 Heraklion, Greece
| | - Jean Muris
- Department of Family Medicine, Care and Public Health Research Institute (CAPHRI), Maastricht University, 6229 Maastricht, The Netherlands
| | - Spilios Manolakopoulos
- Department of Gastroenterology, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Papatheodoridis
- Gastroenterology Department, Medical School, National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", 11527 Athens, Greece
| | - Dimitrios Samonakis
- Clinic of Gastroenterology & Hepatology, University Hospital of Heraklion, 70013 Heraklion, Greece
| | - Emmanouil Symvoulakis
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Ioanna Tsiligianni
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, 71003 Heraklion, Greece
| |
Collapse
|
17
|
Banerjee T, Sarkar A, Ali SZ, Bhowmik R, Karmakar S, Halder AK, Ghosh N. Bioprotective Role of Phytocompounds Against the Pathogenesis of Non-alcoholic Fatty Liver Disease to Non-alcoholic Steatohepatitis: Unravelling Underlying Molecular Mechanisms. PLANTA MEDICA 2024; 90:675-707. [PMID: 38458248 DOI: 10.1055/a-2277-4805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD), with a global prevalence of 25%, continues to escalate, creating noteworthy concerns towards the global health burden. NAFLD causes triglycerides and free fatty acids to build up in the liver. The excessive fat build-up causes inflammation and damages the healthy hepatocytes, leading to non-alcoholic steatohepatitis (NASH). Dietary habits, obesity, insulin resistance, type 2 diabetes, and dyslipidemia influence NAFLD progression. The disease burden is complicated due to the paucity of therapeutic interventions. Obeticholic acid is the only approved therapeutic agent for NAFLD. With more scientific enterprise being directed towards the understanding of the underlying mechanisms of NAFLD, novel targets like lipid synthase, farnesoid X receptor signalling, peroxisome proliferator-activated receptors associated with inflammatory signalling, and hepatocellular injury have played a crucial role in the progression of NAFLD to NASH. Phytocompounds have shown promising results in modulating hepatic lipid metabolism and de novo lipogenesis, suggesting their possible role in managing NAFLD. This review discusses the ameliorative role of different classes of phytochemicals with molecular mechanisms in different cell lines and established animal models. These compounds may lead to the development of novel therapeutic strategies for NAFLD progression to NASH. This review also deliberates on phytomolecules undergoing clinical trials for effective management of NAFLD.
Collapse
Affiliation(s)
- Tanmoy Banerjee
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Sk Zeeshan Ali
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Rudranil Bhowmik
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Sanmoy Karmakar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| | - Amit Kumar Halder
- Dr. B. C. Roy College of Pharmacy and Allied Health Sciences, Dr. Meghnad Saha Sarani, Bidhannagar, Durgapur, West Bengal, India
| | - Nilanjan Ghosh
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata, India
| |
Collapse
|
18
|
Bo T, Gao L, Yao Z, Shao S, Wang X, Proud CG, Zhao J. Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease. Cell Metab 2024; 36:947-968. [PMID: 38718757 DOI: 10.1016/j.cmet.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 01/22/2024] [Accepted: 04/09/2024] [Indexed: 06/26/2024]
Abstract
Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled.
Collapse
Affiliation(s)
- Tao Bo
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ling Gao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Zhenyu Yao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Shanshan Shao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Xuemin Wang
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia
| | - Christopher G Proud
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia.
| | - Jiajun Zhao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China.
| |
Collapse
|
19
|
Fan L, Zhao L, Zhu Y, Li L, Yang X, Ma P, Liu J, Zhao Q, Li X. Hydroxytyrosol ameliorates stress-induced liver injury through activating autophagy via HDAC1/2 inhibition. Food Funct 2024; 15:5103-5117. [PMID: 38680105 DOI: 10.1039/d4fo01027b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
Hydroxytyrosol (HT), a phenolic extra-virgin olive oil compound used as a food supplement, has been recognized to protect liver function and alleviate stress-induced depressive-like behaviors. However, its protective effects against stress-induced liver injury (SLI) remain unknown. Here, the anti-SLI effect of HT was evaluated in mice with chronic unpredictable mild stress-induced SLI. Network pharmacology combined with molecular docking was used to clarify the underlying mechanism of action of HT against SLI, followed by experimental verification. The results showed that accompanying with the alleviation of HT on stress-induced depressive-like behaviors, HT was confirmed to exert the protective effects against SLI, as represented by reduced serum corticosterone (CORT), aspartate aminotransferase and alanine aminotransferase activities, as well as repair of liver structure, inhibition of oxidative homeostasis collapse, and inflammation reaction in the liver. Furthermore, core genes including histone deacetylase 1 and 2 (HDAC1/2), were identified as potential targets of HT in SLI based on bioinformatic screening and simulation. Consistently, HT significantly inhibited HDAC1/2 expression to maintain mitochondrial dysfunction in an autophagy-dependent manner, which was confirmed in a CORT-induced AML-12 cell injury and SLI mice models combined with small molecule inhibitors. We provide the first evidence that HT inhibits HDAC1/2 to induce autophagy in hepatocytes for maintaining mitochondrial dysfunction, thus preventing inflammation and oxidative stress for exerting an anti-SLI effect. This constitutes a novel therapeutic modality to synchronously prevent stress-induced depression-like behaviors and liver injury, supporting the advantaged therapeutic potential of HT.
Collapse
Affiliation(s)
- Li Fan
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lijuan Zhao
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Yangbo Zhu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lin Li
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xueping Yang
- Department of Integrated Traditional Chinese and Western Medicine, Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ping Ma
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Jian Liu
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qingwei Zhao
- Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xiaobo Li
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
- Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational Research, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| |
Collapse
|
20
|
Brouwers B, Rao G, Tang Y, Rodríguez Á, Glass LC, Hartman ML. Incretin-based investigational therapies for the treatment of MASLD/MASH. Diabetes Res Clin Pract 2024; 211:111675. [PMID: 38636848 DOI: 10.1016/j.diabres.2024.111675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 04/15/2024] [Accepted: 04/15/2024] [Indexed: 04/20/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease. It exists as either simple steatosis or its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), formerly, non-alcoholic steatohepatitis (NASH). The global prevalence of MASLD is estimated to be 32% among adults and is projected to continue to rise with increasing rates of obesity, type 2 diabetes, and metabolic syndrome. While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of MASH is therefore directed at slowing, stopping, or reversing the progression of disease. Evidence points to improved liver histology with therapies that result in sustained body weight reduction. Incretin-based molecules, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptor agonists, have shown benefit here, and several are under investigation for MASLD/MASH treatment. In this review, we discuss current published data on GLP-1, GIP/GLP-1, GLP-1/glucagon, and GLP-1/GIP/glucagon RAs in MASLD/MASH, focusing on their efficacy on liver histology, liver fat, and MASH biomarkers.
Collapse
Affiliation(s)
| | - Girish Rao
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | | | | |
Collapse
|
21
|
Peng X, Zhang X, Xu Z, Li L, Mo X, Peng Z, Shan Z, Yan H, Xu J, Liu L. Peripheral amyloid-β clearance mediates cognitive impairment in non-alcoholic fatty liver disease. EBioMedicine 2024; 102:105079. [PMID: 38507874 PMCID: PMC10965463 DOI: 10.1016/j.ebiom.2024.105079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 03/03/2024] [Accepted: 03/08/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a prevalent risk factor for cognitive impairment. Cerebral amyloid-β (Aβ) accumulation, as an important pathology of cognitive impairment, can be caused by impaired Aβ clearance in the periphery. The liver is the primary organ for peripheral Aβ clearance, but the role of peripheral Aβ clearance in NAFLD-induced cognitive impairment remains unclear. METHODS We examined correlations between NAFLD severity, Aβ accumulation, and cognitive performance in female Sprague-Dawley rats. The impact of NAFLD on hepatic Aβ clearance and the involvement of low-density lipoprotein receptor-related protein 1 (LRP-1) were assessed in rat livers and cultured hepatocytes. Additionally, a case-control study, including 549 NAFLD cases and 549 controls (782 males, 316 females), investigated the interaction between NAFLD and LRP-1 rs1799986 polymorphism on plasma Aβ levels. FINDINGS The severity of hepatic steatosis and dysfunction closely correlated with plasma and cerebral Aβ accumulations and cognitive deficits in rats. The rats with NAFLD manifested diminished levels of LRP-1 and Aβ in liver tissue, with these reductions inversely proportional to plasma and cerebral Aβ concentrations and cognitive performance. In vitro, exposure of HepG2 cells to palmitic acid inhibited LRP-1 expression and Aβ uptake, which was subsequently reversed by a peroxisome proliferator-activated receptor α (PPARα) agonist. The case-control study revealed NAFLD to be associated with an increment of 8.24% and 10.51% in plasma Aβ40 and Aβ42 levels, respectively (both P < 0.0001). Moreover, the positive associations between NAFLD and plasma Aβ40 and Aβ42 levels were modified by the LRP-1 rs1799986 polymorphism (P for interaction = 0.0017 and 0.0015, respectively). INTERPRETATION LRP-1 mediates the adverse effect of NAFLD on peripheral Aβ clearance, thereby contributing to cerebral Aβ accumulation and cognitive impairment in NAFLD. FUNDING Major International (Regional) Joint Research Project, National Key Research and Development Program of China, National Natural Science Foundation of China, and the Angel Nutrition Research Fund.
Collapse
Affiliation(s)
- Xiaobo Peng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Xing Zhang
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Zihui Xu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Linyan Li
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Xiaoxing Mo
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Zhao Peng
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Zhilei Shan
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Hong Yan
- Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Jian Xu
- Department of Elderly Health Management, Shenzhen Center for Chronic Disease Control, Shenzhen 518000, China.
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China; Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
| |
Collapse
|
22
|
Zhu S, Wu Z, Wang W, Wei L, Zhou H. A revisit of drugs and potential therapeutic targets against non-alcoholic fatty liver disease: learning from clinical trials. J Endocrinol Invest 2024; 47:761-776. [PMID: 37839037 DOI: 10.1007/s40618-023-02216-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/01/2023] [Indexed: 10/17/2023]
Abstract
PURPOSE Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. Although numerous clinical trials have been conducted over the last few decades, an effective treatment has not been approved yet. Extensive research has accumulated a large amount of data and experience; however, the vast number of clinical trials and new therapeutic targets for NAFLD make it impossible to keep abreast of the relevant information. Therefore, a systematic analysis of the existing trials is necessary. METHODS Here, we reviewed clinical trials on NAFLD registered in the mandated federal database, ClinicalTrials.gov, to generate a detailed overview of the trials related to drugs and therapeutic targets for NAFLD treatment. Following screening for pertinence to therapy, a total of 440 entries were identified that included active trials as well as those that have already been completed, suspended, terminated, or withdrawn. RESULTS We summarize and systematically analyze the state, drug development pipeline, and discovery of treatment targets for NAFLD. We consider possible factors that may affect clinical outcomes. Furthermore, we discussed these results to explore the mechanisms responsible for clinical outcomes. CONCLUSION We summarised the landscape of current clinical trials and suggested the directions for future NAFLD therapy to assist internal medicine specialists in treating the whole clinical spectrum of this highly prevalent liver disease.
Collapse
Affiliation(s)
- S Zhu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Z Wu
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - W Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - L Wei
- School of Life Science, Anhui Medical University, Hefei, 230032, China.
| | - H Zhou
- School of Life Science, Anhui Medical University, Hefei, 230032, China.
| |
Collapse
|
23
|
Desai R, Alvi AT, Vasavada A, Pulakurthi YS, Patel B, Mohammed AS, Doshi S, Ogbu I. Sex and racial disparities in non-alcoholic fatty liver disease-related cardiovascular events: National inpatient sample analysis (2019). World J Cardiol 2024; 16:137-148. [PMID: 38576521 PMCID: PMC10989223 DOI: 10.4330/wjc.v16.i3.137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/15/2024] [Accepted: 02/18/2024] [Indexed: 03/21/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) increases cardiovascular disease (CVD) risk irrespective of other risk factors. However, large-scale cardiovascular sex and race differences are poorly understood. AIM To investigate the relationship between NAFLD and major cardiovascular and cerebrovascular events (MACCE) in subgroups using a nationally representative United States inpatient sample. METHODS We examined National Inpatient Sample (2019) to identify adult hospitalizations with NAFLD by age, sex, and race using ICD-10-CM codes. Clinical and demographic characteristics, comorbidities, and MACCE-related mortality, acute myocardial infarction (AMI), cardiac arrest, and stroke were compared in NAFLD cohorts by sex and race. Multivariable regression analyses were adjusted for sociodemographic characteristics, hospitalization features, and comorbidities. RESULTS We examined 409130 hospitalizations [median 55 (IQR 43-66) years] with NFALD. NAFLD was more common in females (1.2%), Hispanics (2%), and Native Americans (1.9%) than whites. Females often reported non-elective admissions, Medicare enrolment, the median age of 55 (IQR 42-67), and poor income. Females had higher obesity and uncomplicated diabetes but lower hypertension, hyperlipidemia, and complicated diabetes than males. Hispanics had a median age of 48 (IQR 37-60), were Medicaid enrollees, and had non-elective admissions. Hispanics had greater diabetes and obesity rates than whites but lower hypertension and hyperlipidemia. MACCE, all-cause mortality, AMI, cardiac arrest, and stroke were all greater in elderly individuals (P < 0.001). MACCE, AMI, and cardiac arrest were more common in men (P < 0.001). Native Americans (aOR 1.64) and Asian Pacific Islanders (aOR 1.18) had higher all-cause death risks than whites. CONCLUSION Increasing age and male sex link NAFLD with adverse MACCE outcomes; Native Americans and Asian Pacific Islanders face higher mortality, highlighting a need for tailored interventions and care.
Collapse
Affiliation(s)
- Rupak Desai
- Independent Researcher, Atlanta, GA 30079, United States
| | - Ali Tariq Alvi
- Department of Internal Medicine, HCA Florida Westside Hospital, Plantation, FL 33324, United States
| | - Advait Vasavada
- Department of Internal Medicine, M.P. Shah Medical Coll, Jamnagar 361008, India
| | | | - Bhavin Patel
- Department of Internal Medicine, Trinity Health Oakland Hospital, Pontiac, MI 48341, United States
| | - Adil Sarvar Mohammed
- Department of Internal Medicine, Central Michigan University College of Medicine, Saginaw, MI 48602, United States
| | - Shreyans Doshi
- Department of Internal Medicine, UCF College of Medicine HCA GME Consortium, Gainesville, FL 32605, United States
| | - Ikechukwu Ogbu
- Department of Internal Medicine, Mountainview Hospital, Las Vegas, NV 89108, United States.
| |
Collapse
|
24
|
Yorke E. Co-Morbid Hypothyroidism and Liver Dysfunction: A Review. Clin Med Insights Endocrinol Diabetes 2024; 17:11795514241231533. [PMID: 38348020 PMCID: PMC10860496 DOI: 10.1177/11795514241231533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/11/2024] [Indexed: 02/15/2024] Open
Abstract
The liver and thyroid hormones interact at multiple levels to maintain homoeostasis. The liver requires large adequate amounts of thyroid hormones to execute its metabolic functions optimally, and deficiency of thyroid hormones may lead to liver dysfunction. Hypothyroidism has been associated with abnormal lipid metabolism, non-alcoholic fatty liver disease (NAFLD), hypothyroidism-induced myopathy, hypothyroidism-associated gallstones and occasionally, interferon-induced thyroid dysfunction. NAFLD remain an important association with hypothyroidism and further studies are needed that specifically compare the natural course of NAFLD secondary to hypothyroidism and primary NAFLD. Hepatic dysfunction associated with hypothyroidism is usually reverted by normalizing thyroid status. Large scale studies geared towards finding new and effective therapies, especially for NAFLD are needed. The clinician must be aware that there exists overlapping symptomatology between liver dysfunction and severe hypothyroidism which may make delay the diagnosis and treatment of hypothyroidism; this requires a high index of suspicion.
Collapse
Affiliation(s)
- Ernest Yorke
- Department of Medicine & Therapeutics, University of Ghana Medical School, Accra, Ghana
| |
Collapse
|
25
|
Younis MM, Ayoub IM, George MY, Mostafa NM, Eldahshan OA. In vivo hepatoprotective and nephroprotective effects of Stenocarpus sinuatus leaf extract against ifosfamide-induced toxicity in rats. Arch Pharm (Weinheim) 2024; 357:e2300438. [PMID: 37984852 DOI: 10.1002/ardp.202300438] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 10/02/2023] [Accepted: 10/24/2023] [Indexed: 11/22/2023]
Abstract
Ifosfamide (IFOS) is a broad-spectrum chemotherapeutic agent that has been extensively used for breast cancer and other solid tumors. Unfortunately, its use is associated with toxicities of several organs. Stenocarpus sinuatus is an Australian tree belonging to the Proteaceae family. In the current study, the phytochemical constituents of S. sinuatus methanol leaf extract (SSLE) were assessed. In addition, the protective effect of SSLE against IFOS-induced nephrotoxicity and hepatotoxicity was evaluated. Rats were randomly divided into six groups: control, IFOS (50 mg/kg), IFOS + SSLE (100 mg/kg), IFOS + SSLE (200 mg/kg), IFOS + SSLE (400 mg/kg), and SSLE (400 mg/kg). Hepatoprotective and nephroprotective potency of SSLE was assessed using different biochemical parameters. The phytochemical investigation resulted in the isolation of four flavonoid glycosides (kaempferol 3-O-β- d-glucopyranosyl-(1→2)-α- l-rhamnopyranoside, kaempferol 3-O-α-rhamnopyranoside, isorhamnetin 3-O-β- d-glucopyranosyl-(1→2)-α- l-rhamnopyranoside, and quercetin 3-O-β- d-glucopyranosyl-(1→2)-α- l-rhamnopyranoside) and a coumarin (scopoletin). This is the first report on the isolated compounds from the genus Stenocarpus. SSLE showed enhancement of kidney and liver functions and reduction of oxidative stress and inflammation. The histopathology of the investigated organs confirmed the protective effect of SSLE. In conclusion, SSLE is considered as a promising candidate that can be used in defense against the toxic effects of IFOS after further clinical trials.
Collapse
Affiliation(s)
- Mai M Younis
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
| | - Iriny M Ayoub
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
| | - Mina Y George
- Department of Pharmacology, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
| | - Nada M Mostafa
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
| | - Omayma A Eldahshan
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
| |
Collapse
|
26
|
Barisic-Jaman M, Milosevic M, Skurla V, Dohoczky D, Stojic J, Dinjar Kujundzic P, Cigrovski Berkovic M, Majic-Tengg A, Matijaca A, Lucijanic T, Kardum-Pejic M, Pandzic Jaksic V, Marusic S, Grgurevic I. Compensated Advanced Chronic Liver Disease and Steatosis in Patients with Type 2 Diabetes as Assessed through Shear Wave Measurements and Attenuation Measurements. Biomedicines 2024; 12:323. [PMID: 38397925 PMCID: PMC10886655 DOI: 10.3390/biomedicines12020323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/17/2024] [Accepted: 01/28/2024] [Indexed: 02/25/2024] Open
Abstract
Patients with type 2 diabetes (T2D) are at risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the prevalence of compensated advanced chronic liver disease (cACLD) and steatosis in patients with T2D using the new non-invasive diagnostic methods of shear wave measurements (SWMs) and attenuation (ATT) measurements in comparison with those of vibration-controlled transient elastography (VCTE) and the controlled attenuation parameter (CAP), which served as the reference methods. Among 214 T2D patients, steatosis at any grade and cACLD were revealed in 134 (62.6%) and 19 (8.9%) patients, respectively. SWMs showed a high correlation with VCTE (Spearman's ρ = 0.641), whereas SWMs produced lower (mean of -0.7 kPa) liver stiffness measurements (LSMs) overall. At a LSM of >11.0 kPa (Youden), SWMs had an AUROC of 0.951 that was used to diagnose cACLD (defined as a LSM of >15 kPa through VCTE) with 84.2% sensitivity and 96.4% specificity. The performance of ATT measurements in diagnosing liver steatosis at any grade (defined as the CAP of ≥274 dB/m) was suboptimal (AUROC of 0.744 at the ATT measurement cut-off of >0.63 dB/cm/MHz (Youden) with 59% sensitivity and 81.2% specificity). In conclusion, the prevalence of liver steatosis and previously unrecognized cACLD in patients with T2D is high and SWMs appear to be a reliable diagnostic method for this purpose, whereas further investigation is needed to optimize the diagnostic performance of ATT measurements.
Collapse
Affiliation(s)
- Mislav Barisic-Jaman
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.B.-J.); (V.S.); (D.D.); (J.S.); (P.D.K.); (I.G.)
| | - Marko Milosevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.B.-J.); (V.S.); (D.D.); (J.S.); (P.D.K.); (I.G.)
| | - Viktoria Skurla
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.B.-J.); (V.S.); (D.D.); (J.S.); (P.D.K.); (I.G.)
| | - David Dohoczky
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.B.-J.); (V.S.); (D.D.); (J.S.); (P.D.K.); (I.G.)
| | - Josip Stojic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.B.-J.); (V.S.); (D.D.); (J.S.); (P.D.K.); (I.G.)
| | - Petra Dinjar Kujundzic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.B.-J.); (V.S.); (D.D.); (J.S.); (P.D.K.); (I.G.)
| | - Maja Cigrovski Berkovic
- Department of Endocrinology, Diabetes, Diseases of Metabolism and Clinical Pharmacology, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.C.B.); (A.M.-T.); (A.M.); (T.L.); (M.K.-P.); (S.M.)
- Department of Sport and Exercise Medicine, Faculty of Kinesiology, University of Zagreb, 10000 Zagreb, Croatia
| | - Ana Majic-Tengg
- Department of Endocrinology, Diabetes, Diseases of Metabolism and Clinical Pharmacology, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.C.B.); (A.M.-T.); (A.M.); (T.L.); (M.K.-P.); (S.M.)
| | - Ana Matijaca
- Department of Endocrinology, Diabetes, Diseases of Metabolism and Clinical Pharmacology, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.C.B.); (A.M.-T.); (A.M.); (T.L.); (M.K.-P.); (S.M.)
| | - Tomo Lucijanic
- Department of Endocrinology, Diabetes, Diseases of Metabolism and Clinical Pharmacology, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.C.B.); (A.M.-T.); (A.M.); (T.L.); (M.K.-P.); (S.M.)
| | - Mirjana Kardum-Pejic
- Department of Endocrinology, Diabetes, Diseases of Metabolism and Clinical Pharmacology, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.C.B.); (A.M.-T.); (A.M.); (T.L.); (M.K.-P.); (S.M.)
| | - Vlatka Pandzic Jaksic
- Department of Endocrinology, Diabetes, Diseases of Metabolism and Clinical Pharmacology, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.C.B.); (A.M.-T.); (A.M.); (T.L.); (M.K.-P.); (S.M.)
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Srecko Marusic
- Department of Endocrinology, Diabetes, Diseases of Metabolism and Clinical Pharmacology, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.C.B.); (A.M.-T.); (A.M.); (T.L.); (M.K.-P.); (S.M.)
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia; (M.B.-J.); (V.S.); (D.D.); (J.S.); (P.D.K.); (I.G.)
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
| |
Collapse
|
27
|
Camacho-Cardenosa A, Clavero-Jimeno A, Martin-Olmedo JJ, Amaro-Gahete F, Cupeiro R, Cejudo MTG, García Pérez PV, Hernández-Martínez C, Sevilla-Lorente R, De-la-O A, López-Vázquez A, Molina-Fernandez M, Carneiro-Barrera A, Garcia F, Rodríguez-Nogales A, Gálvez Peralta JJ, Cabeza R, Martín-Rodríguez JL, Muñoz-Garach A, Muñoz-Torres M, Labayen I, Ruiz JR. Time-restricted eating and supervised exercise for improving hepatic steatosis and cardiometabolic health in adults with obesity: protocol for the TEMPUS randomised controlled trial. BMJ Open 2024; 14:e078472. [PMID: 38267239 PMCID: PMC10824004 DOI: 10.1136/bmjopen-2023-078472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 12/21/2023] [Indexed: 01/26/2024] Open
Abstract
INTRODUCTION Metabolic dysfunction-associated steatotic liver disease is a major public health problem considering its high prevalence and its strong association with extrahepatic diseases. Implementing strategies based on an intermittent fasting approach and supervised exercise may mitigate the risks. This study aims to investigate the effects of a 12-week time-restricted eating (TRE) intervention combined with a supervised exercise intervention, compared with TRE or supervised exercise alone and with a usual-care control group, on hepatic fat (primary outcome) and cardiometabolic health (secondary outcomes) in adults with obesity. METHODS AND ANALYSIS An anticipated 184 adults with obesity (50% women) will be recruited from Granada (south of Spain) for this parallel-group, randomised controlled trial (TEMPUS). Participants will be randomly designated to usual care, TRE alone, supervised exercise alone or TRE combined with supervised exercise, using a parallel design with a 1:1:1:1 allocation ratio. The TRE and TRE combined with supervised exercise groups will select an 8-hour eating window before the intervention and will maintain it over the intervention. The exercise alone and TRE combined with exercise groups will perform 24 sessions (2 sessions per week+walking intervention) of supervised exercise combining resistance and aerobic high-intensity interval training. All participants will receive nutritional counselling throughout the intervention. The primary outcome is change from baseline to 12 weeks in hepatic fat; secondary outcomes include measures of cardiometabolic health. ETHICS AND DISSEMINATION This study was approved by Granada Provincial Research Ethics Committee (CEI Granada-0365-N-23). All participants will be asked to provide written informed consent. The findings will be disseminated in scientific journals and at international scientific conferences. TRIAL REGISTRATION NUMBER NCT05897073.
Collapse
Affiliation(s)
- Alba Camacho-Cardenosa
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
| | - Antonio Clavero-Jimeno
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
| | - Juan J Martin-Olmedo
- Department of Physiology, Faculty of Pharmacy, Institute of Nutrition and Food Technology, Biomedical Research Centre, University of Granada, Granada, Spain
| | - Francisco Amaro-Gahete
- Instituto de Investigación Biosanitaria, Ibs, University of Granada, Granada, Spain
- Department of Physiology, Faculty of Medicine, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío Cupeiro
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
- LFE Research Group, Department of Health and Human Performance, Faculty of Physical Activity and Sport Science (INEF), Universidad Politécnica de Madrid, Madrid, Spain
| | | | | | - Carlos Hernández-Martínez
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
| | - Raquel Sevilla-Lorente
- Department of Physiology, Faculty of Pharmacy, Institute of Nutrition and Food Technology, Biomedical Research Centre, University of Granada, Granada, Spain
| | - Alejandro De-la-O
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Alejandro López-Vázquez
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
| | - Marcos Molina-Fernandez
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
| | | | - Federico Garcia
- Instituto de Investigación Biosanitaria, Ibs, University of Granada, Granada, Spain
- Servicio de Microbiología, Hospital Universitario San Cecilio, Granada, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERinfecc), Instituto de Salud Carlos III, Madrid, Spain
| | - Alba Rodríguez-Nogales
- Instituto de Investigación Biosanitaria, Ibs, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain
| | - Julio Juan Gálvez Peralta
- Instituto de Investigación Biosanitaria, Ibs, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Pharmacology, Center for Biomedical Research, Granada, Spain
| | - Rafael Cabeza
- Department of Electrical, Electronic and Communications Engineering, Public University of Navarre, Pamplona, Spain
| | | | - Araceli Muñoz-Garach
- Instituto de Investigación Biosanitaria, Ibs, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Endocrinology and Nutrition Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain
| | - Manuel Muñoz-Torres
- Instituto de Investigación Biosanitaria, Ibs, University of Granada, Granada, Spain
- Endocrinology and Nutrition Unit, Hospital Universitario San Cecilio, Granada, Spain
- Department of Medicine, Faculty of Medicine, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERfes), Instituto de Salud Carlos III, Madrid, Spain
| | - Idoia Labayen
- Navarre Institute of Health Research, Pamplona, Spain
- Institute for Sustainability & Food Chain Innovation, Department of Health Sciences, Public University of Navarre, Pamplona, Spain
| | - Jonatan R Ruiz
- Department of Physical Education and Sports, Faculty of Sport Sciences, Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
- Instituto de Investigación Biosanitaria, Ibs, University of Granada, Granada, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
28
|
Kwan SH, Gonzalez de Mejia E. The Potential of the Adzuki Bean ( Vigna angularis) and Its Bioactive Compounds in Managing Type 2 Diabetes and Glucose Metabolism: A Narrative Review. Nutrients 2024; 16:329. [PMID: 38276567 PMCID: PMC10820388 DOI: 10.3390/nu16020329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/20/2024] [Accepted: 01/21/2024] [Indexed: 01/27/2024] Open
Abstract
Type 2 diabetes (T2D) is a common noncommunicable disease. In the United States alone, 37 million Americans had diabetes in 2017. The adzuki bean (Vigna angularis), a legume, has been reported to possess antidiabetic benefits. However, the extent and specific mechanisms through which adzuki bean consumption may contribute to T2D prevention and management remain unclear. Therefore, the aim of this narrative review is to analyze current evidence supporting the utilization of adzuki beans in the diet as a strategy for preventing and managing T2D. Animal studies have demonstrated a positive impact of adzuki beans on managing T2D. However, supporting data from humans are limited. Conversely, the potential of adzuki bean consumption in preventing T2D via modulating two T2D risk factors (obesity and dyslipidemia) also lacks conclusive evidence. Animal studies have suggested an inconsistent and even contradictory relationship between adzuki bean consumption and the management of obesity and dyslipidemia, in which both positive and negative relationships are reported. In sum, based on the existing scientific literature, this review found that the effects of adzuki bean consumption on preventing and managing T2D in humans remain undetermined. Consequently, human randomized controlled trials are needed to elucidate the potential benefits of the adzuki bean and its bioactive components in the prevention and management of T2D.
Collapse
Affiliation(s)
- Shu Hang Kwan
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA;
| | - Elvira Gonzalez de Mejia
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA;
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA
| |
Collapse
|
29
|
Yang RX, Fan JG. Metabolic comorbidities, endocrine—Diabetes, polycystic ovarian syndrome, thyroid dysfunction. METABOLIC STEATOTIC LIVER DISEASE 2024:123-136. [DOI: 10.1016/b978-0-323-99649-5.00004-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
30
|
Koh JH, Wang M, Suzuki H, Muthiah M, Ng CH, Huang DQ. NAFLD and NAFLD-related HCC in Asia: Burden and Surveillance. J Clin Exp Hepatol 2024; 14:101213. [PMID: 38076360 PMCID: PMC10701133 DOI: 10.1016/j.jceh.2023.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/30/2023] [Indexed: 06/21/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is rapidly emerging as a leading etiology of chronic liver disease (CLD) in Asia. The increasing incidence of NAFLD is projected to drive a surge in NAFLD-related hepatocellular carcinoma (HCC). A notable characteristic of NAFLD-HCC is its capacity for development in individuals without cirrhosis in more than a third of patients. Most practice guidelines recommend biannual ultrasound screening for patients with cirrhosis. In cases of severe limitations to ultrasound visualisation, cross-sectional abdominal imaging may be warranted. Improved strategies for HCC risk stratification are required for people with NAFLD but without cirrhosis. In this Review, we discuss the evolving trends of NAFLD and HCC in Asia, and implications for surveillance.
Collapse
Affiliation(s)
- Jia H. Koh
- Department of Medicine, National University Hospital, Singapore, Singapore
| | - Meng Wang
- Department of Medicine, National University Hospital, Singapore, Singapore
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Cheng H. Ng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Daniel Q. Huang
- NAFLD Research Center, University of California at San Diego, USA
| |
Collapse
|
31
|
Marchianò S, Biagioli M, Bordoni M, Morretta E, Di Giorgio C, Vellecco V, Roselli R, Bellini R, Massa C, Cari L, Urbani G, Ricci P, Monti MC, Giordano A, Brancaleone V, Bucci M, Zampella A, Distrutti E, Cieri E, Cirino G, Fiorucci S. Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G-Protein Bile Acid Receptor 1/Farnesoid X Receptor Agonism and Statins in the Treatment of Nonalcoholic Fatty Liver Disease. J Am Heart Assoc 2023; 12:e031241. [PMID: 37996988 PMCID: PMC10727350 DOI: 10.1161/jaha.123.031241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/31/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND Patients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid-activated receptors exploited in the treatment of nonalcoholic fatty liver disease: whether dual GPBAR1/FXR agonists synergize with statins in the treatment of the liver and cardiovascular components of nonalcoholic fatty liver disease is unknown. METHODS AND RESULTS Investigations of human aortic samples obtained from patients who underwent surgery for aortic aneurysms and Gpbar1-/-, Fxr-/-, and dual Gpbar1-/-Fxr-/- mice demonstrated that GPBAR1 and FXR are expressed in the aortic wall and regulate endothelial cell/macrophage interactions. The expression of GPBAR1 in the human endothelium correlated with the expression of inflammatory biomarkers. Mice lacking Fxr and Gpbar1-/-/Fxr-/- display hypotension and aortic inflammation, along with altered intestinal permeability that deteriorates with age, and severe dysbiosis, along with dysregulated bile acid synthesis. Vasomotor activities of aortic rings were altered by Gpbar1 and Fxr gene ablation. In apolipoprotein E-/- and wild-type mice, BAR502, a dual GPBAR1/FXR agonist, alone or in combination with atorvastatin, reduced cholesterol and low-density lipoprotein plasma levels, mitigated the development of liver steatosis and aortic plaque formation, and shifted the polarization of circulating leukocytes toward an anti-inflammatory phenotype. BAR502/atorvastatin reversed intestinal dysbiosis and dysregulated bile acid synthesis, promoting a shift of bile acid pool composition toward FXR antagonists and GPBAR1 agonists. CONCLUSIONS FXR and GPBAR1 maintain intestinal, liver, and cardiovascular homeostasis, and their therapeutic targeting with a dual GPBAR1/FXR ligand and atorvastatin holds potential in the treatment of liver and cardiovascular components of nonalcoholic fatty liver disease.
Collapse
Affiliation(s)
- Silvia Marchianò
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Michele Biagioli
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Martina Bordoni
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Elva Morretta
- Department of PharmacyUniversity of SalernoSalernoItaly
| | | | | | | | - Rachele Bellini
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Carmen Massa
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Luigi Cari
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Ginevra Urbani
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Patrizia Ricci
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | | | | | | | | | - Angela Zampella
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | | | - Enrico Cieri
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Giuseppe Cirino
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | - Stefano Fiorucci
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| |
Collapse
|
32
|
Zeng J, Jin Q, Yang J, Yang RX, Zhang RN, Zhao J, Fan JG. Prevalence and incidence of MAFLD and associated anthropometric parameters among prepubertal children of the Shanghai Birth Cohort. Hepatol Int 2023; 17:1416-1428. [PMID: 37728728 DOI: 10.1007/s12072-023-10574-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 07/21/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND AND AIM Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease in adolescent and adult population. However, the epidemiologic data of MAFLD in prepubertal children remain limited. This study aimed to investigate the prevalence and incidence of MAFLD and assess the role of anthropometric parameters in identifying and predicting MAFLD in this population. METHODS Children from the Shanghai Birth Cohort Study who underwent an 8-year follow-up with anthropometric measurements and transient elastography FibroScan-502 examination (M probe, Echosens, Paris, France) were enrolled. Some of them also completed a 5-year follow-up. Diagnosis of fatty liver disease (FLD) was based on the controlled attenuation parameter (CAP) value exceeding 248 dB/m, and MAFLD was defined as FLD combined with obesity or central obesity. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of anthropometric parameters for MAFLD. RESULTS A total of 848 children (431 boys) from the Shanghai Birth Cohort Study were followed up for 8 years, and among them, 385 children (189 boys) also participated in the 5-year follow-up. The prevalence of FLD and MAFLD at 5 years old was 3.90% and 0.52%, respectively, while at 8 years old, the prevalence rates increased to 5.07% for FLD and 3.42% for MAFLD. The 8-year-old children with MAFLD exhibited significantly higher weight, body mass index (BMI), chest circumference, waist circumference, hip circumference, waist-to-height ratio, waist-to-hip ratio, and liver stiffness measurement compared to those without MAFLD (all p < 0.05). The incidence rates of FLD and MAFLD at 8 years old, considering the 5-year follow-up data, were 3.78% (14/370) and 3.13% (12/383), respectively. Obese or centrally obese children at 5 years old had a higher incidence of FLD and MAFLD at the 8-year follow-up. Waist circumference and BMI showed significant associations with the presence and incidence of MAFLD, respectively, with the largest AUC values in ROC curve analysis. In addition, chest circumference was significantly associated with MAFLD in obese children. CONCLUSION This study provides insights into the incidence and prevalence of MAFLD in prepubertal children. It underscores the importance of anthropometric parameters in identifying and predicting MAFLD in this population. Further research encompassing a broader age range and incorporating these indicators and additional metabolic markers is necessary to enhance the understanding and management of MAFLD in children.
Collapse
Affiliation(s)
- Jing Zeng
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Qian Jin
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Jing Yang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Rui-Xu Yang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Rui-Nan Zhang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China
| | - Jian Zhao
- The Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China.
- Department of Maternal and Child Health, School of Public Health, Shanghai Jiao Tong University, Shanghai, China.
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, No.1665, Kongjiang Road, Yangpu District, Shanghai, 200092, China.
| |
Collapse
|
33
|
Yoo SH, Park JY, Lee HS, Lee HW, Lee JI. Risk of dementia in the elderly with non-alcoholic fatty liver disease: A nested case-control study in the Republic of Korea. ANNALS OF THE ACADEMY OF MEDICINE, SINGAPORE 2023; 52:570-579. [PMID: 38920146 DOI: 10.47102/annals-acadmedsg.202379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/27/2024]
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) is known to be associated with metabolic syndrome of which diabetes is an important component. Although diabetes is a known risk factor for dementia, studies on the association between NAFLD and dementia still produce conflicting results. This study aimed to determine whether NAFLD would be a risk factor for the development of dementia in an elderly population. Method This study included 107,369 subjects aged ≥60 years in the Korean National Health Insurance Service-Senior cohort, entered in 2009 and followed up until 2015. NAFLD was diagnosed by calculating fatty liver index (FLI). Subjects were screened for dementia at baseline using a Korean Dementia Screening Questionnaire, and dementia was diagnosed using ICD-10 codes. Controls were randomly selected at a ratio of 1:5 from individuals who were at risk of becoming the case subjects at the time of selection. Results From 107,369 subjects, 65,690 stroke- and dementia-free subjects without chronic hepatitis B or C or excessive alcohol drinking were selected for evaluation. Having NAFLD, determined by FLI, was associated with increased risk of dementia development (adjusted odds ratio [AOR] 1.493; 95% confidence interval [CI] 1.214-1.836). The increased risk of dementia in NAFLD subjects was independent of type 2 diabetes (AOR 1.421; 95% CI 1.013-1.994, in subjects with diabetes: AOR 1.540; 95% CI 1.179- 2.010, in subjects without diabetes). Conclusion In this population-based nested case-control study, having NAFLD increased the risk of dementia in elderly individuals, independent of accompanying diabetes.
Collapse
Affiliation(s)
- Sung Hwan Yoo
- Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Gangnam Severance Hospital, Yonsei University College of Medicine, Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea
| | - Ju-Young Park
- Department of Statistics and Data Science, Yonsei University, Seoul, Republic of Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Gangnam Severance Hospital, Yonsei University College of Medicine, Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea
| | - Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Gangnam Severance Hospital, Yonsei University College of Medicine, Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea
| |
Collapse
|
34
|
Zhang Y, Fang XM. The pan-liver network theory: From traditional chinese medicine to western medicine. CHINESE J PHYSIOL 2023; 66:401-436. [PMID: 38149555 DOI: 10.4103/cjop.cjop-d-22-00131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023] Open
Abstract
In traditional Chinese medicine (TCM), the liver is the "general organ" that is responsible for governing/maintaining the free flow of qi over the entire body and storing blood. According to the classic five elements theory, zang-xiang theory, yin-yang theory, meridians and collaterals theory, and the five-viscera correlation theory, the liver has essential relationships with many extrahepatic organs or tissues, such as the mother-child relationships between the liver and the heart, and the yin-yang and exterior-interior relationships between the liver and the gallbladder. The influences of the liver to the extrahepatic organs or tissues have been well-established when treating the extrahepatic diseases from the perspective of modulating the liver by using the ancient classic prescriptions of TCM and the acupuncture and moxibustion. In modern medicine, as the largest solid organ in the human body, the liver has the typical functions of filtration and storage of blood; metabolism of carbohydrates, fats, proteins, hormones, and foreign chemicals; formation of bile; storage of vitamins and iron; and formation of coagulation factors. The liver also has essential endocrine function, and acts as an immunological organ due to containing the resident immune cells. In the perspective of modern human anatomy, physiology, and pathophysiology, the liver has the organ interactions with the extrahepatic organs or tissues, for example, the gut, pancreas, adipose, skeletal muscle, heart, lung, kidney, brain, spleen, eyes, skin, bone, and sexual organs, through the circulation (including hemodynamics, redox signals, hepatokines, metabolites, and the translocation of microbiota or its products, such as endotoxins), the neural signals, or other forms of pathogenic factors, under normal or diseases status. The organ interactions centered on the liver not only influence the homeostasis of these indicated organs or tissues, but also contribute to the pathogenesis of cardiometabolic diseases (including obesity, type 2 diabetes mellitus, metabolic [dysfunction]-associated fatty liver diseases, and cardio-cerebrovascular diseases), pulmonary diseases, hyperuricemia and gout, chronic kidney disease, and male and female sexual dysfunction. Therefore, based on TCM and modern medicine, the liver has the bidirectional interaction with the extrahepatic organ or tissue, and this established bidirectional interaction system may further interact with another one or more extrahepatic organs/tissues, thus depicting a complex "pan-hepatic network" model. The pan-hepatic network acts as one of the essential mechanisms of homeostasis and the pathogenesis of diseases.
Collapse
Affiliation(s)
- Yaxing Zhang
- Department of Physiology; Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong; Issue 12th of Guangxi Apprenticeship Education of Traditional Chinese Medicine (Shi-Cheng Class of Guangxi University of Chinese Medicine), College of Continuing Education, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Xian-Ming Fang
- Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine (Guangxi Hospital of Integrated Chinese Medicine and Western Medicine, Ruikang Clinical Faculty of Guangxi University of Chinese Medicine), Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| |
Collapse
|
35
|
Herranz JM, López-Pascual A, Clavería-Cabello A, Uriarte I, Latasa MU, Irigaray-Miramon A, Adán-Villaescusa E, Castelló-Uribe B, Sangro B, Arechederra M, Berasain C, Avila MA, Fernández-Barrena MG. Comprehensive analysis of epigenetic and epitranscriptomic genes' expression in human NAFLD. J Physiol Biochem 2023; 79:901-924. [PMID: 37620598 PMCID: PMC10636027 DOI: 10.1007/s13105-023-00976-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 07/19/2023] [Indexed: 08/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes' expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.
Collapse
Affiliation(s)
- Jose M Herranz
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Amaya López-Pascual
- Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Alex Clavería-Cabello
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Iker Uriarte
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - M Ujúe Latasa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Ainara Irigaray-Miramon
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Elena Adán-Villaescusa
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Borja Castelló-Uribe
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
| | - Bruno Sangro
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - María Arechederra
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Carmen Berasain
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Matías A Avila
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
| | - Maite G Fernández-Barrena
- Hepatology Laboratory, Solid Tumors Program, CIMA, CCUN, University of Navarra, Pamplona, Spain.
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
| |
Collapse
|
36
|
Myint M, Oppedisano F, De Giorgi V, Kim BM, Marincola FM, Alter HJ, Nesci S. Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions. J Transl Med 2023; 21:757. [PMID: 37884933 PMCID: PMC10605416 DOI: 10.1186/s12967-023-04627-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 10/14/2023] [Indexed: 10/28/2023] Open
Abstract
Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH.
Collapse
Affiliation(s)
| | - Francesca Oppedisano
- Department of Health Sciences, Institute of Research for Food Safety and Health, University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | - Valeria De Giorgi
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA
| | | | | | - Harvey J Alter
- Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, USA
| | - Salvatore Nesci
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, Italy.
| |
Collapse
|
37
|
Zhang J, Zhang Y, Ren Z, Yan D, Li G. The role of TRIM family in metabolic associated fatty liver disease. Front Endocrinol (Lausanne) 2023; 14:1210330. [PMID: 37867509 PMCID: PMC10585262 DOI: 10.3389/fendo.2023.1210330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 09/20/2023] [Indexed: 10/24/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) ranks among the most prevalent chronic liver conditions globally. At present, the mechanism of MAFLD has not been fully elucidated. Tripartite motif (TRIM) protein is a kind of protein with E3 ubiquitin ligase activity, which participates in highly diversified cell activities and processes. It not only plays an important role in innate immunity, but also participates in liver steatosis, insulin resistance and other processes. In this review, we focused on the role of TRIM family in metabolic associated fatty liver disease. We also introduced the structure and functions of TRIM proteins. We summarized the TRIM family's regulation involved in the occurrence and development of metabolic associated fatty liver disease, as well as insulin resistance. We deeply discussed the potential of TRIM proteins as targets for the treatment of metabolic associated fatty liver disease.
Collapse
Affiliation(s)
- Jingyue Zhang
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China
| | - Yingming Zhang
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China
| | - Ze Ren
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China
| | - Dongmei Yan
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Guiying Li
- Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China
| |
Collapse
|
38
|
Jiang N, Zhang S, Chu J, Yang N, Lu M. Association between body roundness index and non-alcoholic fatty liver disease detected by Fibroscan in America. J Clin Lab Anal 2023; 37:e24973. [PMID: 37850486 PMCID: PMC10681427 DOI: 10.1002/jcla.24973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 03/27/2023] [Accepted: 10/03/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease (NAFLD) and obesity is worldwide on the rise. Body roundness index (BRI), as a newly developed anthropometric indicator, has been recently reported to identify obesity. However, it is still unclear whether BRI is associated with the prevalence of NAFLD. METHODS Data were from the National Health and Nutrition Examination Survey (NHANES) 2017-2018. NAFLD was diagnosed based on hepatic steatosis defined by CAP values ≥274 dB/m. Multivariable logistic regression analysis was performed to detect the association between BRI and the odds of NAFLD. Subgroup analysis stratified by age, gender, BMI, and race was further conducted. To explore the potential ability of BRI in predicting NAFLD, the area under the curve (AUC) of BRI was calculated by receiver operating characteristic (ROC) analysis. RESULTS Among the 4467 study participants, 1718 (38.5%) were diagnosed with NAFLD. Compared to the non-NAFLD group, participants with NAFLD had a higher level of BRI. The positive associations between BRI and NAFLD were detected in all three models (mode 1: OR = 1.71, 95% CI: 1.65-1.78, p < 0.0001; mode 2: OR = 1.78, 95% CI: 1.71-1.86, p < 0.0001; mode3: OR = 1.23, 95% CI: 1.11-1.35, p < 0.0001). The positive association steadily existed in different subgroups after stratified by age, gender, and BMI. Moreover, the non-linear association between BRI and NAFLD was detected, presenting inverted U-shaped curves. Furthermore, BRI had a high predictive value (AUC = 0.807) in identifying NAFLD. CONCLUSIONS BRI was positively associated with the prevalence of NAFLD among individuals in America, regardless of age, gender, and BMI. Besides, BRI presented a high ability for identifying NAFLD.
Collapse
Affiliation(s)
- Ningning Jiang
- Department of Internal MedicineThe Second Hospital of Ninghai City, Chengguan Hospital of Ninghai CityNingboZhejiangChina
| | - Shengguo Zhang
- Department of Infectionthe Third Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
| | - Jinguo Chu
- Department of General MedicineThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Naibin Yang
- Department of Hepatology and Infectious DiseasesThe First Affiliated Hospital of Ningbo UniversityNingboZhejiangChina
| | - Mingqin Lu
- Department of Infectious DiseasesThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiangChina
| |
Collapse
|
39
|
Dos Santos BG, Miranda RA, Saavedra LPJ, Francisco FA, Ribeiro MVG, Oliveira Ferreira AR, Ferreira-Junior MD, Cavalcante KVN, Xavier CH, de Moura EG, Lisboa PC, Mota APCD, Pedrino GR, Armitage JA, Mathias PCDF, Palma-Rigo K, Gomes RM. Puberty as a DOHaD programming window: high-fat diet induces long-term hepatic dysfunction in male rats. J Dev Orig Health Dis 2023; 14:614-622. [PMID: 37955113 DOI: 10.1017/s2040174423000272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
The aim of this study was to evaluate whether high-fat (HF) diet intake during puberty can program obesity as well as generate glucose imbalance and hepatic metabolic dysfunctions in adult life. Male Wistar rats were randomly assigned into two groups: rats fed standard chow (NF) and rats fed a HF from postnatal 30-day-old (PND30) until PND60. Then, both groups were fed a standard chow from PND60 until PND120. Euthanasia and samples collections occurred at PND120. HF animals were overweight (+11%) and had increased adiposity, hyperphagia (+12%), hyperglycaemia (+13%), hyperinsulinemia (+69%), and hypertriglyceridemia (+34%). Plasma glucose levels during intravenous glucose tolerance test (ivGTT) and intraperitoneal insulin tolerance test (ipITT) were also higher in the HF group, whereas Kitt was significantly lower (-34%), suggesting reduced insulin sensitivity. In the same sense, HF animals present pancreatic islets hypertrophy and high β-cell mass. HF animals also had a significant increase in blood glucose levels during pyruvate tolerance test, indicating increased gluconeogenesis. Hepatic morphology analyses showed an increase in lipid inclusion in the HF group. Moreover, PEPCK and FAS protein expression were higher in the livers of the HF animals (+79% and + 37%, respectively). In conclusion, HF during puberty causes obese phenotype leading to glucose dyshomeostasis and nonalcoholic fatty liver disease, which can be related to the overexpression of proteins PEPCK and FAS.
Collapse
Affiliation(s)
- Beatriz Gonçalves Dos Santos
- Department of Physiological Sciences, Laboratory of Endocrine Physiology and Metabolism, Federal University of Goiás, Goiânia, GO, Brazil
| | - Rosiane Aparecida Miranda
- Department of Physiological Sciences, Laboratory of Endocrine Physiology, Institute of Biology Roberto Alcantara Gomes, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Lucas Paulo Jacinto Saavedra
- Department of Biotechnology, Genetics and Cell Biology, Laboratory of Secretion Cell Biology, State University of Maringá, Maringá, Brazil
| | - Flávio Andrade Francisco
- Department of Biotechnology, Genetics and Cell Biology, Laboratory of Secretion Cell Biology, State University of Maringá, Maringá, Brazil
| | - Maiara Vanusa Guedes Ribeiro
- Department of Biotechnology, Genetics and Cell Biology, Laboratory of Secretion Cell Biology, State University of Maringá, Maringá, Brazil
| | - Anna Rebeka Oliveira Ferreira
- Department of Biotechnology, Genetics and Cell Biology, Laboratory of Secretion Cell Biology, State University of Maringá, Maringá, Brazil
| | - Marcos Divino Ferreira-Junior
- Department of Physiological Sciences, Laboratory of Endocrine Physiology and Metabolism, Federal University of Goiás, Goiânia, GO, Brazil
| | - Keilah Valéria Naves Cavalcante
- Department of Physiological Sciences, Laboratory of Endocrine Physiology and Metabolism, Federal University of Goiás, Goiânia, GO, Brazil
| | | | - Egberto Gaspar de Moura
- Department of Physiological Sciences, Laboratory of Endocrine Physiology, Institute of Biology Roberto Alcantara Gomes, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Patrícia Cristina Lisboa
- Department of Physiological Sciences, Laboratory of Endocrine Physiology, Institute of Biology Roberto Alcantara Gomes, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Ariel Penha Carvalho da Mota
- Department of Physiological Sciences, Laboratory of Endocrine Physiology and Metabolism, Federal University of Goiás, Goiânia, GO, Brazil
| | | | | | - Paulo Cezar de Freitas Mathias
- Department of Biotechnology, Genetics and Cell Biology, Laboratory of Secretion Cell Biology, State University of Maringá, Maringá, Brazil
| | - Kesia Palma-Rigo
- Department of Biotechnology, Genetics and Cell Biology, Laboratory of Secretion Cell Biology, State University of Maringá, Maringá, Brazil
| | - Rodrigo Mello Gomes
- Department of Physiological Sciences, Laboratory of Endocrine Physiology and Metabolism, Federal University of Goiás, Goiânia, GO, Brazil
| |
Collapse
|
40
|
Huang L, Bai Q, Wang Z, Zhang X, Liu K, Cui J, Du L, Liu S, Fu Y, Wang H, Li D, Sun H. Carbon Dots as Potential Therapeutic Agents for Treating Non-Alcoholic Fatty Liver Disease and Associated Inflammatory Bone Loss. Bioconjug Chem 2023; 34:1704-1715. [PMID: 37639623 DOI: 10.1021/acs.bioconjchem.3c00362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most significant metabolic diseases worldwide and is associated with heightened systemic inflammation, which has been shown to foster the development of extrahepatic complications. So far, there is no definitive, effective, and safe treatment for NAFLD. Although antidiabetic agents show potential for treating NAFLD, their efficacy is significantly limited by inadequate liver accumulation at safe doses and unwanted side effects. Herein, we demonstrate that pharmacologically active carbon dots (MCDs) derived from metformin can selectively accumulate in the liver and ameliorate NAFLD by activating hepatic PPARα expression while maintaining an excellent biosafety. Interestingly, MCDs can also improve the function of extrahepatic organs and tissues, such as alleviating alveolar inflammatory bone loss, in the process of treating NAFLD. This study proposes a feasible and safe strategy for designing pharmacologically active MCDs to target the liver, which regulates lipid metabolism and systemic inflammation, thereby treating NAFLD and its related extrahepatic complications.
Collapse
Affiliation(s)
- Lei Huang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| | - Qinzhu Bai
- Department of Radiology, The Second Hospital of Jilin University, Changchun 130041, P.R. China
| | - Zhuoran Wang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| | - Xu Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| | - Kexuan Liu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| | - Jing Cui
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| | - Liuyi Du
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| | - Shuchen Liu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| | - Yunhe Fu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun 130062, P.R. China
| | - Huan Wang
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P.R. China
| | - Daowei Li
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| | - Hongchen Sun
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun 130021, P.R. China
| |
Collapse
|
41
|
El-Eshmawy MM. Impact of obesity on liver function tests: is nonalcoholic fatty liver disease the only player? A review article. Porto Biomed J 2023; 8:e228. [PMID: 37846300 PMCID: PMC10575409 DOI: 10.1097/j.pbj.0000000000000228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 07/21/2023] [Accepted: 07/24/2023] [Indexed: 10/18/2023] Open
Abstract
Objectives Obesity and nonalcoholic fatty liver disease (NAFLD) are common worldwide health problems with a strong relationship in between. NAFLD is currently the most common cause of abnormal liver function tests (LFT) because of obesity pandemic. The question is NAFLD the only player of abnormal LFT in obesity? Methodology This article reviews the most important topics regarding the derangements of LFT in obesity through a PubMed search strategy for all English-language literature. Results The reported abnormal LFT in obesity were increased serum levels of transaminases (alanine aminotransaminase, aspartate aminotransaminase), gamma glutamyl transferase, and alkaline phosphatase and decreased serum levels of bilirubin and albumin. Besides novel potential hepatic markers of NAFLD/NASH such as triglycerides/high-density lipoprotein cholesterol ratio, sex hormone-binding globulin, fibroblast growth factor 21, and markers of hepatocyte apoptosis i.e. cytokeratin 18 and microribonucleic acids (miRNAs). Beyond NAFLD, there are other underlying players for the abnormal LFT in obesity such as oxidative stress, inflammation, and insulin resistance. Conclusion Derangements of LFT in obesity are attributed to NAFLD but also to obesity itself and its related oxidative stress, insulin resistance, and chronic inflammatory state. Abnormal LFT predict more than just liver disease.
Collapse
Affiliation(s)
- Mervat M. El-Eshmawy
- Department of Internal Medicine, Mansoura Specialized Medical Hospital, Faculty of Medicine, Mansoura University, Egypt
| |
Collapse
|
42
|
Qiu J, Kuang M, Yang R, Yu C, He S, Sheng G, Zou Y. The newly proposed alanine aminotransferase to high-density lipoprotein cholesterol ratio has shown effectiveness in identifying non-alcoholic fatty liver disease. Front Endocrinol (Lausanne) 2023; 14:1239398. [PMID: 37727457 PMCID: PMC10505795 DOI: 10.3389/fendo.2023.1239398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 08/14/2023] [Indexed: 09/21/2023] Open
Abstract
Objective Alanine aminotransferase (ALT) and high-density lipoprotein cholesterol (HDL-C) are important predictive factors for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyze the association between the ALT/HDL-C ratio and NAFLD. Methods We conducted a retrospective analysis of data from 14,251 individuals participating in the NAGALA project's health screening program. The presence of NAFLD was diagnosed based on the participants' alcohol consumption status and liver ultrasonography images. Multivariable logistic regression models were used to assess the association between the ALT/HDL-C ratio and NAFLD. Receiver operating characteristic (ROC) analysis was performed to determine and compare the effectiveness of ALT, HDL-C, the aspartate aminotransferase to HDL-C (AST/HDL-C) ratio, the gamma-glutamyl transferase to HDL-C (GGT/HDL-C) ratio and the ALT/HDL-C ratio in identifying NAFLD. Results We observed a significant positive association between the ALT/HDL-C ratio and the prevalence of NAFLD. For each standard deviation (SD) increase in the ALT/HDL-C ratio, the adjusted odds ratio (OR) for NAFLD among the participants was 3.05 [95% confidence interval (CI): 2.63, 3.53], with the highest quartile of ALT/HDL-C ratio having a 9.96-fold increased risk compared to the lowest quartile. In further subgroup analyses stratified by gender, age, and waist circumference (WC), we observed a significantly higher risk of NAFLD associated with the ALT/HDL-C ratio among individuals aged ≥45 years, males, and those who were abdominal obesity. Furthermore, based on the results of ROC analysis, we found that the ALT/HDL-C ratio [area under the curves (AUC): 0.8553] was significantly superior to ALT, HDL-C, AST/HDL-C ratio and GGT/HDL-C ratio in identifying NAFLD (All Delong P<0.05); the threshold of suggested ALT/HDL-C ratio for identifying NAFLD was 15.97. Conclusion This population-based study demonstrates a positive association between the ALT/HDL-C ratio and NAFLD. The ALT/HDL-C ratio can effectively identify individuals with NAFLD.
Collapse
Affiliation(s)
- Jiajun Qiu
- Department of Internal Medicine, Medical College of Nanchang University, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi, China
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Maobin Kuang
- Department of Internal Medicine, Medical College of Nanchang University, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi, China
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Ruijuan Yang
- Department of Internal Medicine, Medical College of Nanchang University, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi, China
- Department of Endocrinology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Changhui Yu
- Department of Internal Medicine, Medical College of Nanchang University, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi, China
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Shiming He
- Department of Internal Medicine, Medical College of Nanchang University, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi, China
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Guotai Sheng
- Jiangxi Provincial Geriatric Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
- Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| | - Yang Zou
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China
| |
Collapse
|
43
|
Chambergo-Michilot D, Rodrigo-Gallardo PK, Huaman MR, Vasquez-Chavesta AZ, Salinas-Sedo G, Toro-Huamanchumo CJ. Hypertension and Histopathology Severity of Non-Alcoholic Fatty Liver Disease Among Adults with Obesity: A Cross-Sectional Study. Clin Exp Gastroenterol 2023; 16:129-136. [PMID: 37601009 PMCID: PMC10437097 DOI: 10.2147/ceg.s402498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 06/13/2023] [Indexed: 08/22/2023] Open
Abstract
Background Cardiovascular diseases are responsible for the majority of deaths resulting from non-alcoholic fatty liver disease (NAFLD). NAFLD is associated with hypertension and this is a key predictor of severe liver outcomes and an indicator of nonspecific portal fibrosis. Aim To assess the association between hypertension and NAFLD severity. Methods We conducted a secondary analysis of data from Peruvian adults with obesity and NAFLD who attended a Peruvian bariatric center. The severity of NAFLD was assessed using the Fatty Liver Inhibition of Progression algorithm / Steatosis, Activity and Fibrosis score. Hypertension was determined by either being recorded in the medical records or if the patient had a systolic pressure ≥ 140 mmHg or diastolic pressure ≥ 90 mmHg. To evaluate the association of interest, we calculated crude and adjusted prevalence ratios (aPR) using Poisson generalized linear models with logarithmic link function and robust variances. For the multivariable models, we adjusted for age, sex, physical activity and smoking. Results Our study included 234 participants. The prevalence of hypertension was 19.2%, while the prevalence of severe NAFLD was 46.2%. After adjusting for confounders, the prevalence of hypertension was found to be significantly higher in the severe NAFLD group compared to the non-severe group (aPR = 1.33; 95% CI: 1.03-1.74). When stratified by the presence of metabolic syndrome (MetS), the association remained significant only in the group without MetS (aPR = 1.80; 95% CI: 1.05-3.11). Conclusion We found an association between hypertension and severe NAFLD in adults with obesity, particularly in those without MetS.
Collapse
Affiliation(s)
| | | | - Mariella R Huaman
- Facultad de Medicina Humana, Universidad Nacional Mayor de San Marcos, Lima, Peru
| | | | | | - Carlos J Toro-Huamanchumo
- Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud, Universidad San Ignacio de Loyola, Lima, Peru
- OBEMET Centro de Obesidad y Salud Metabólica, Lima, Peru
| |
Collapse
|
44
|
Su YH, Chien KL, Yang SH, Chia WT, Chen JH, Chen YC. Nonalcoholic Fatty Liver Disease Is Associated With Decreased Bone Mineral Density in Adults: A Systematic Review and Meta-Analysis. J Bone Miner Res 2023; 38:1092-1103. [PMID: 37254266 DOI: 10.1002/jbmr.4862] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 05/04/2023] [Accepted: 05/21/2023] [Indexed: 06/01/2023]
Abstract
This systematic review and meta-analysis aimed to investigate the effect of nonalcoholic fatty liver disease (NAFLD) on bone mineral density (BMD) and the risk of osteoporosis and osteoporotic fracture in adults. We searched PubMed, MEDLINE, Embase, CINAHL, Web of Science, Cochrane Library, and Scopus for observational studies published from inception to January 2023 that reported adjusted effect sizes of NAFLD on BMD, osteopenia/osteoporosis, and osteoporotic fracture. The data were synthesized using multilevel and random-effects models. A total of 19 studies were included; of these, nine (21,294 participants) evaluated the effect of NAFLD on BMD, six (133,319 participants) investigated the risk of osteoporosis, and five (227,901 participants) assessed the risk of osteoporotic fracture. This meta-analysis showed that NAFLD was associated with decreased BMD (mean difference -0.019 g/cm2 , 95% confidence interval [CI] -0.036 to -0.002, I2 = 93%) and increased risks of osteoporosis (adjusted risk ratio [RR] = 1.28, 95% CI 1.08 to 1.52, I2 = 84%) and osteoporotic fractures (adjusted RR = 1.17, 95% CI 1.00 to 1.37, I2 = 67%). Subgroup analyses revealed that NAFLD had a significantly detrimental effect on BMD in men and on the BMD of the femoral neck and total hip. Stratified analyses by ethnicity demonstrated that NAFLD was not associated with BMD, osteoporosis, or osteoporotic fracture in non-Asian populations. The publication bias of all included studies was low; however, there was considerable heterogeneity among the studies, warranting a careful interpretation of the findings. Overall, our results suggest that NAFLD is associated with decreased BMD and an increased risk of osteoporosis or osteoporotic fractures. Male sex and the BMD of the femoral neck and total hip may be potential risk factors for decreased BMD in adults with NAFLD. Additionally, ethnic disparities were observed between Asian and non-Asian populations regarding BMD and osteoporotic fractures. © 2023 American Society for Bone and Mineral Research (ASBMR).
Collapse
Affiliation(s)
- Ying-Hao Su
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei City, Taiwan
- Department of Orthopaedic Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu City, Taiwan
| | - Kuo-Liong Chien
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei City, Taiwan
| | - Shu-Hua Yang
- Department of Orthopaedic Surgery, National Taiwan University Hospital, Taipei City, Taiwan
| | - Wei-Tso Chia
- Department of Orthopaedic Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu City, Taiwan
| | - Jen-Hau Chen
- Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Ching Chen
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei City, Taiwan
| |
Collapse
|
45
|
Terasaka Y, Takahashi H, Amano K, Fujisaki K, Kita S, Kato K, Nakayama K, Yamashita Y, Nakamura S, Anzai K. Change in Liver Fibrosis Associates with Progress of Diabetic Nephropathy in Patients with Nonalcoholic Fatty Liver Disease. Nutrients 2023; 15:3248. [PMID: 37513666 PMCID: PMC10386534 DOI: 10.3390/nu15143248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023] Open
Abstract
Diabetic nephropathy (DN) is a major complication of diabetes. Nonalcoholic fatty liver disease (NAFLD) is common in diabetes, and liver fibrosis is a prognostic risk factor for NAFLD. The interaction between DN and liver fibrosis in NAFLD remains unclear. In 189 patients with DN and NAFLD who received an education course about diabetic nephropathy, liver fibrosis was evaluated using the fibrosis-4 (FIB-4) index. The association between the outcome of DN and changes in liver fibrosis was examined. The FIB-4 index was maintained at the baseline level in patients with improved DN, while it was increased in other patients. The ΔFIB-4 index was positively correlated with changes in albuminuria and proteinuria (ρ = 0.22, p = 0.004). In a multivariate analysis, changes in albuminuria and proteinuria were associated with the ΔFIB-4 index (p = 0.002). Patients with a progressive FIB-4 index category from baseline to 5 years showed a lower event-free survival rate after 5 years than patients with an improved FIB-4 index category (p = 0.037). The outcome of DN is associated with changes in liver fibrosis in patients with diabetes, NAFLD and DN. Developing a preventive and therapeutic approach for these conditions is required.
Collapse
Affiliation(s)
- Yoshiko Terasaka
- Department of Internal Medicine, Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Hirokazu Takahashi
- Department of Internal Medicine, Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Kazushi Amano
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Koshiro Fujisaki
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
- Fujisaki Clinic, Kagoshima 891-0141, Japan
| | - Shotaro Kita
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Kaori Kato
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
- Ryutokukai Medical Corp, Tsuruta Hospital, Miyazaki 881-0016, Japan
| | - Koujin Nakayama
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Yuko Yamashita
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Shuji Nakamura
- Internal Medicine, Heiwadai Hospital, Miyazaki 880-0034, Japan
| | - Keizo Anzai
- Department of Internal Medicine, Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| |
Collapse
|
46
|
Pagano S, Bakker SJL, Juillard C, Dullaart RPF, Vuilleumier N. Serum Level of Cytokeratin 18 (M65) as a Prognostic Marker of High Cardiovascular Disease Risk in Individuals with Non-Alcoholic Fatty Liver Disease. Biomolecules 2023; 13:1128. [PMID: 37509164 PMCID: PMC10377236 DOI: 10.3390/biom13071128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/10/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Alterations in apoptosis, as reflected by circulating Cytokeratin 18 (CK18), are involved in the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis and atherogenesis. We aimed to explore the discriminant accuracy of Cytokeratin 18 (CK18, including M65 and M30 forms) for an elevated fatty liver index (FLI) as a validated proxy of NAFLD, and cardiovascular disease (CVD) risk in the general population. Both serum CK18 forms were measured using a commercial immunoassay in randomly selected samples from 312 participants of the PREVEND general population cohort. FLI ≥ 60 was used to indicate NAFLD. Framingham Risk Score (FRS) and the SCORE2 were used to estimate the 10-year risk of CVD. The Receiver Operating Characteristic (ROC) curve, linear/logistic regression models, and Spearman's correlations were used. Intricate associations were found between CK18, FLI, and CVD risk scores. While M30 was the only independent predictor of FLI ≥ 60, M65 best discriminated NAFLD individuals at very-high 10-year CVD risk according to SCORE2 (AUC: 0.71; p = 0.001). Values above the predefined manufacturer cutoff (400 U/L) were associated with an independent 5-fold increased risk (adjusted odds ratio: 5.44, p = 0.01), with a negative predictive value of 93%. Confirming that NAFLD is associated with an increased CVD risk, our results in a European general population-based cohort suggest that CK18 M65 may represent a candidate biomarker to identify NAFLD individuals at low CVD risk.
Collapse
Affiliation(s)
- Sabrina Pagano
- Division of Laboratory Medicine, Diagnostics Department, Geneva University Hospitals, 1205 Geneva, Switzerland;
- Department of Medicine Specialties, Medical Faculty, Geneva University, 1211 Geneva, Switzerland;
| | - Stephan J. L. Bakker
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
| | - Catherine Juillard
- Department of Medicine Specialties, Medical Faculty, Geneva University, 1211 Geneva, Switzerland;
| | - Robin P. F. Dullaart
- Division of Endocrinology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands;
| | - Nicolas Vuilleumier
- Division of Laboratory Medicine, Diagnostics Department, Geneva University Hospitals, 1205 Geneva, Switzerland;
- Department of Medicine Specialties, Medical Faculty, Geneva University, 1211 Geneva, Switzerland;
| |
Collapse
|
47
|
Li L, Song Y, Shi Y, Sun L. Thyroid Hormone Receptor-β Agonists in NAFLD Therapy: Possibilities and Challenges. J Clin Endocrinol Metab 2023; 108:1602-1613. [PMID: 36746649 DOI: 10.1210/clinem/dgad072] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 02/01/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a progressive metabolic liver disease with an unknown pathogenesis and no FDA-approved drug treatment to date. Hypothyroidism has been identified as a risk factor for NAFLD as thyroxine is required for regulating metabolism in adults. Thyroxine has been shown to reduce fat in the livers of murine models with experimentally induced NAFLD. The use of synthetic thyroxine has been shown to increase lipid metabolism leading to weight loss; however, thyroxine has also been shown to cause many side effects, especially in the heart. Overcoming these cardiac side effects involves designing agonists specific to one of the 2 gene subtypes for the thyroid hormone (TH) receptor (TR), TRβ. While the other TH receptor subtype, TRα, is mainly expressed in the heart and is responsible for thyroxine's cardiac function, TRβ is mainly expressed in the liver and is involved in liver function. Using TRβ-specific agonists to treat NAFLD can prevent cardiac and other adverse side effects. Several TRβ-specific agonists have shown positive therapeutic effects in NAFLD animal models and have entered clinical trials. We seek to provide a comprehensive updated reference of TRβ-specific agonists in this review and explore the future therapeutic potential of TRβ-specific activation in the treatment of NAFLD.
Collapse
Affiliation(s)
- Limei Li
- Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
| | - Yan Song
- Department of Endocrinology and Metabolism, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yongquan Shi
- Department of Endocrinology and Metabolism, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Liangliang Sun
- Department of Endocrinology and Metabolism, Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| |
Collapse
|
48
|
Sheptulina AF, Yafarova AA, Golubeva JA, Mamutova EM, Kiselev AR, Drapkina OM. Clinically Meaningful Fatigue and Depression Are Associated with Sarcopenia in Patients with Non-Alcoholic Fatty Liver Disease. J Pers Med 2023; 13:932. [PMID: 37373921 DOI: 10.3390/jpm13060932] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/28/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Sarcopenia is thought to be related to an increased risk of non-alcoholic steatohepatitis and advanced liver fibrosis. Our cross-sectional single-center study was designed to analyze the prevalence of sarcopenia in patients with NAFLD and possible influencing factors. METHODS A survey on the presence of sarcopenia, fatigue, anxiety, and depression, along with a quality-of-life (QoL) assessment, was forwarded by email to 189 outpatients. Demographics, anthropometric and clinical data (laboratory test results and abdomen complete ultrasound protocol), performed within 2-4 weeks prior to the enrollment, were obtained. RESULTS Sarcopenia (defined as SARC-F score ≥ 4) was identified in 17 (15.7%) patients, all of them (100%) females, with median age (interquartile range) 56 (51-64) years. These patients had a poorer metabolic state (greater values of waist and hip circumferences, body mass index, and HOMA-IR) and significantly poorer QoL, specifically, regarding the physical component of health, compared with NAFLD patients without sarcopenia. Multivariate analysis showed that depression (OR = 1.25, 95% CI: 1.02-1.53, p = 0.035) and clinically meaningful fatigue (OR = 1.14, 95% CI: 1.04-1.26, p = 0.008) were the factors independently associated with sarcopenia in patients with NAFLD. CONCLUSION Sarcopenia is associated with depression and fatigue rather than with the severity of liver disease alone and may negatively affect QoL in patients with NAFLD.
Collapse
Affiliation(s)
- Anna F Sheptulina
- National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Russia
- Department of Therapy and Preventive Medicine, A.I. Evdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| | - Adel A Yafarova
- National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Russia
| | - Julia A Golubeva
- National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Russia
| | - Elvira M Mamutova
- National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Russia
| | - Anton R Kiselev
- National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Russia
| | - Oxana M Drapkina
- National Medical Research Center for Therapy and Preventive Medicine, Moscow 101990, Russia
- Department of Therapy and Preventive Medicine, A.I. Evdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
| |
Collapse
|
49
|
Yu Y, Yu Y, Wang Y, Chen Y, Wang N, Wang B, Lu Y. Nonalcoholic fatty liver disease and type 2 diabetes: an observational and Mendelian randomization study. Front Endocrinol (Lausanne) 2023; 14:1156381. [PMID: 37223039 PMCID: PMC10200946 DOI: 10.3389/fendo.2023.1156381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/10/2023] [Indexed: 05/25/2023] Open
Abstract
Introduction Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are both chronic multisystem diseases that cause tremendous health burdens worldwide. Previous epidemiological studies have found a bidirectional relationship between these two diseases; however, their causality remains largely unknown. We aim to examine the causal relationship between NAFLD and T2DM. Methods The observational analysis included 2,099 participants from the SPECT-China study and 502,414 participants from the UK Biobank. Logistic regression and Cox regression models were used to examine the bidirectional association between NAFLD and T2DM. Two-sample Mendelian randomization (MR) analyses were conducted to investigate the causal effects of the two diseases using summary statistics of genome-wide association studies from the UK Biobank for T2DM and the FinnGen study for NAFLD. Results During the follow-up, 129 T2DM cases and 263 NAFLD cases were observed in the SPECT-China study, and 30,274 T2DM cases and 4,896 NAFLD cases occurred in the UK Biobank cohort. Baseline NAFLD was associated with an increased risk of incident T2DM in both studies (SPECT-China: OR: 1.74 (95% confidence interval (CI): 1.12-2.70); UK Biobank: HR: 2.16 (95% CI: 1.82-2.56)), while baseline T2DM was associated with incident NAFLD in the UK Biobank study only (HR: 1.58). Bidirectional MR analysis showed that genetically determined NAFLD was significantly associated with an increased risk of T2DM (OR: 1.003 (95% CI: 1.002-1.004, p< 0.001)); however, there was no evidence of an association between genetically determined T2DM and NAFLD (OR: 28.1 (95% CI: 0.7-1,143.0)). Conclusions Our study suggested the causal effect of NAFLD on T2DM development. The lack of a causal association between T2DM and NAFLD warrants further verification.
Collapse
Affiliation(s)
| | | | | | | | - Ningjian Wang
- *Correspondence: Ningjian Wang, ; Bin Wang, ; Yingli Lu,
| | - Bin Wang
- *Correspondence: Ningjian Wang, ; Bin Wang, ; Yingli Lu,
| | - Yingli Lu
- *Correspondence: Ningjian Wang, ; Bin Wang, ; Yingli Lu,
| |
Collapse
|
50
|
Hokkanen A, Hämäläinen H, Laitinen TM, Laitinen TP. Decreased liver-to-spleen ratio in low-dose computed tomography as a biomarker of fatty liver disease reflects risk for myocardial ischaemia. EUROPEAN HEART JOURNAL. IMAGING METHODS AND PRACTICE 2023; 1:qyad016. [PMID: 39044791 PMCID: PMC11240163 DOI: 10.1093/ehjimp/qyad016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 07/31/2023] [Indexed: 07/25/2024]
Abstract
Aims A strong association between fatty liver disease (FLD) and coronary artery disease is consistently reported. Our aim was to evaluate whether FLD diagnosed using low-dose non-contrast computed tomography (LDCT), as a by-product of myocardial perfusion imaging (MPI), is associated with myocardial ischaemia or left ventricular function parameters. Methods and results We analysed 742 patients who had undergone MPI using single photon emission computed tomography (SPECT) and LDCT. A liver-to-spleen ratio (in Hounsfield units) of <1 was defined as FLD. Myocardial ischaemia was defined as a summed difference score (SDS) ≥3. Left ventricular size and systolic function were assessed from the electrocardiogram-gated SPECT. FLD patients were younger (63 vs. 68 years) and had a higher body mass index (34.6 vs. 29.0 kg/m2) and a higher SDS (2.65 vs. 1.63), P < 0.001 for all. Independently of several possible confounding factors including traditional risk factors, patients with FLD had a 1.70-fold risk of ischaemia (95% confidence interval 1.11-2.58, P = 0.014). Left ventricular end-diastolic volume (109 vs. 109 mL) and ejection fraction (61 vs. 61%) were comparable in those with and without FLD (non-significant for both). Conclusions With the help of LDCT, it is possible to identify FLD, which is associated with an increased risk of myocardial ischaemia. Therefore, evaluation of FLD from LDCT is recommended along with MPI.
Collapse
Affiliation(s)
- A Hokkanen
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Puijonlaaksontie 2, 70200 Kuopio, Finland
- School of Medicine, University College Cork, Ireland
| | - H Hämäläinen
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Puijonlaaksontie 2, 70200 Kuopio, Finland
| | - T M Laitinen
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Puijonlaaksontie 2, 70200 Kuopio, Finland
| | - T P Laitinen
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Puijonlaaksontie 2, 70200 Kuopio, Finland
- Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| |
Collapse
|