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Ahmed M. Ramadan Fasting and Complications of Metabolic Dysfunction-Associated Steatotic Liver Disease: Impacts on Liver Cirrhosis and Heart Failure. J Clin Med 2025; 14:1841. [PMID: 40142648 PMCID: PMC11942711 DOI: 10.3390/jcm14061841] [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: 02/17/2025] [Revised: 03/03/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
BACKGROUND Metabolic-dysfunction-associated steatotic liver disease (MASLD) and heart failure are two intersecting growing pandemics. Studies have demonstrated a strong association between MASLD and heart failure. Liver cirrhosis is a well-recognized complication of MASLD. This study aimed to summarize the potential effects of Ramadan fasting on MASLD, liver cirrhosis, and heart failure. The author searched the SCOPUS and PubMed databases using specific terms. The literature review focused on research articles published in English from 2000 to 2024. Twenty-two articles were selected for this narrative review. Ramadan fasting reduced serum cholesterol serum levels, improved symptoms of heart failure and reduced anthropometric measurements. However, it increased ascitic fluid production and plasma bilirubin levels and might increase the risk of hepatic encephalopathy and upper gastrointestinal haemorrhage in liver cirrhosis. Ramadan fasting might improve symptoms of heart failure and might decrease the risk of heart failure in patients with MASLD. Further research studies are needed to confirm the efficacy and evaluate the safety of Ramadan fasting in patients with heart failure and liver cirrhosis.
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Affiliation(s)
- Musaab Ahmed
- College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates;
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
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Xu J, Cheng X, Wang Q, Zhang F, Ren X, Huang K, Hu Y, Gao R, Yang K, Yin J, Yang B, He X, Li Y. Artemether Ameliorates Non-Alcoholic Steatohepatitis by Restraining Cross-Talk Between Lipotoxicity-Induced Hepatic Hepatocytes and Macrophages. Phytother Res 2025; 39:604-618. [PMID: 39609107 DOI: 10.1002/ptr.8393] [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: 07/02/2024] [Revised: 10/08/2024] [Accepted: 11/09/2024] [Indexed: 11/30/2024]
Abstract
Non-alcoholic steatohepatitis (NASH) has no effective treatment drug. Our previous study initially found that artemether (Art) treatment significantly attenuates NSAH by regulating liver lipid metabolism. This study further elucidates new mechanisms of Art in improving liver inflammation and provides evidence for drug repurposing. Herein, we utilized HFHF diet-induced animal model and macrophage models to detect the mechanisms of Art in NASH. We confirmed that Art significantly reduced hepatic steatosis, injury, and fibrosis in a high-fat high-fructose (HFHF) diet-induced animal model. Art significantly suppressed the activation of inflammatory macrophages and secretion of pro-inflammatory cytokine (IL-1β) by reducing serum double-stranded DNA (dsDNA) levels and triggering the AIM2/Caspase-1/GSDMD signaling in vivo. dsDNA-induced Caspase-1 and PI-positive cells pyroptosis, AIM2 inflammasome activation, IL-1β, and IL-18 secretion increase were inhibited by Art in vitro. Furthermore, we found Art effectively suppressed mitochondrial DNA (mtDNA), a typical form of dsDNA, released from free fatty acid (FFA)-stressed hepatocytes, which further inhibited AIM2 inflammasome mediated-pyroptosis through decreasing the cleavage of Caspase-1/GSDMD/IL-1β. Moreover, inhibition of the AIM2 gene partly reversed the inhibitory effect of Art on macrophage pyroptosis. Impaired mitochondrial structure and function were confirmed in FFA-stressed hepatocytes and the HFHF-diet-induced NASH mouse model, which was reversed by Art treatment. The present study provides evidence for Art as a potential anti-pyroptosis therapeutic agent for NASH treatment.
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Affiliation(s)
- Jia Xu
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Xiaoyan Cheng
- Institute of Analysis and Testing, Beijing Academy of Science and Technology, Beijing, China
| | - Qi Wang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Feng Zhang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Xinxin Ren
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Kunlun Huang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yanzhou Hu
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Ruxin Gao
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Kun Yang
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jingya Yin
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Bingqing Yang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyun He
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yue Li
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Xu J, Li QQ, Yang S, Teng HD, Lu ZY, Gu YZ, Xi JH, Mei ZN, Chen Y, Yang GZ. Garcibracgluinols A-C, structurally intriguing polycyclic polyprenylated acylphloroglucinols from Garcinia bracteata alleviate hepatocyte lipid accumulation and insulin resistance. J Mol Struct 2025; 1323:140755. [DOI: 10.1016/j.molstruc.2024.140755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hur YK, Lee HE, Yoo JY, Park YN, Lee IH, Bae YS. NADPH oxidase 4-SH3 domain-containing YSC84-like 1 complex participates liver inflammation and fibrosis. Free Radic Biol Med 2025; 227:246-259. [PMID: 39645205 DOI: 10.1016/j.freeradbiomed.2024.12.021] [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: 08/31/2024] [Revised: 11/19/2024] [Accepted: 12/04/2024] [Indexed: 12/09/2024]
Abstract
There is growing evidence that NADPH oxidase 4 (Nox4) in hepatocytes contributes to liver inflammation and fibrosis during the development of metabolic dysfunction-associated steatohepatitis (MASH). However, how Nox4 is regulated and leads to liver pathogenesis is unclear. Our previous studies showed that the cytosolic protein SH3 domain-containing Ysc84-like 1 (SH3YL1) regulates Nox4 activity. Here, we asked whether SH3YL1 also participates in liver inflammation and fibrosis during MASH development. We generated that whole body SH3YL1 knockout (SH3YL1-/-), Nox4 knockout (Nox4-/-) mice, and the hepatocyte-specific SH3YL1 conditional knockout (Alb-Cre/SH3YL1fl/fl) mice were fed a methionine/choline-deficient (MCD) diet to induce liver inflammation and fibrosis in pathogenesis of MASH. Palmitate-stimulated primary SH3YL1-and Nox4-deficient hepatocytes and hepatic stellate cells (HSCs) did not generate H2O2. While the liver of MCD diet-fed wild type (WT) mice demonstrated elevated 3-nitrotyrosine as a protein oxidation and 4-hydroxynonenal adducts as a lipid oxidation and increased liver inflammation, hepatocyte apoptosis, and liver fibrosis, these events were markedly reduced in SH3YL1-/-, Nox4-/-, and Alb-Cre/SH3YL1fl/fl mice. The MCD diet-fed WT mice also showed elevated hepatocyte expression of SH3YL1 protein. Similarly, liver biopsies from MASH patients demonstrated strong hepatocyte SH3YL1 protein expression, whereas hepatocytes from patients with steatosis weakly expressed SH3YL1 and histologically normal patient hepatocytes exhibited very little SH3YL1 expression. The Nox4-SH3YL1 complex in murine hepatocytes elevates their H2O2 production, which promotes the liver inflammation, hepatocyte apoptosis, and liver fibrosis that characterize MASH. This axis may also participate in MASH in humans.
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Affiliation(s)
- Yeo Kyu Hur
- Department of Life Sciences, Ewha Womans University, 52 Ewhayeodae-Gil, Seodaemoon-Gu, Seoul, 03760, South Korea
| | - Hye Eun Lee
- Celros Biotech, 52 Ewhayeodae-Gil, Seodaemoon-Gu, Seoul, 03760, South Korea
| | - Jung-Yeon Yoo
- Department of Life Sciences, Ewha Womans University, 52 Ewhayeodae-Gil, Seodaemoon-Gu, Seoul, 03760, South Korea
| | - Young Nyun Park
- Department of Pathology Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-Gu, Seoul, 03722, South Korea
| | - In Hye Lee
- Department of Life Sciences, Ewha Womans University, 52 Ewhayeodae-Gil, Seodaemoon-Gu, Seoul, 03760, South Korea.
| | - Yun Soo Bae
- Department of Life Sciences, Ewha Womans University, 52 Ewhayeodae-Gil, Seodaemoon-Gu, Seoul, 03760, South Korea; Celros Biotech, 52 Ewhayeodae-Gil, Seodaemoon-Gu, Seoul, 03760, South Korea.
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Bril F, Berg G, Barchuk M, Nogueira JP. Practical Approaches to Managing Dyslipidemia in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. J Lipid Atheroscler 2025; 14:5-29. [PMID: 39911965 PMCID: PMC11791423 DOI: 10.12997/jla.2025.14.1.5] [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: 12/25/2023] [Revised: 02/15/2024] [Accepted: 03/10/2024] [Indexed: 02/07/2025] Open
Abstract
Dyslipidemia is a major risk factor for cardiovascular disease, and its impact may be exacerbated when accompanied by metabolic dysfunction-associated steatotic liver disease (MASLD). The simultaneous management of these conditions poses multiple challenges for healthcare providers. Insulin resistance has been implicated in the pathogenesis of both dyslipidemia and MASLD, necessitating a holistic approach to managing dyslipidemia, glucose levels, body weight, and MASLD. This review explores the intricate pathophysiological relationship between MASLD and dyslipidemia. It also examines current guidance regarding the use of lipid-lowering agents (including statins, ezetimibe, fibrates, omega-3 polyunsaturated fatty acids, and proprotein convertase subtilisin/kexin type 9 inhibitors) as well as glucose-lowering medications (such as pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors) in patients with MASLD, with or without metabolic dysfunction-associated steatohepatitis (MASH), and dyslipidemia. Additionally, the review addresses the potential of emerging drugs to concurrently target both MASLD/MASH and dyslipidemia. Our hope is that a deeper understanding of the mechanisms underlying MASLD and dyslipidemia may assist clinicians in the management of these complex cases.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gabriela Berg
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Magali Barchuk
- Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Laboratorio de Lípidos y Aterosclerosis, Universidad de Buenos Aires, Buenos Aires, Argentina
- CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Patricio Nogueira
- Centro de Investigación en Endocrinología, Nutrición y Metabolismo (CIENM), Facultad de Ciencias de la Salud, Universidad Nacional de Formosa, Formosa, Argentina
- Universidad Internacional de las Américas, San José, Costa Rica
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Uchiyama A, Kon K, Morinaga M, Fukada H, Yaginuma R, Fukuhara K, Yamashina S, Iwabuchi K, Ikejima K. Palmitic acid induces insulin resistance and oxidative stress-mediated cell injury through accumulation of lipid rafts in murine hepatocytes. Biochem Biophys Res Commun 2024; 745:151242. [PMID: 39732125 DOI: 10.1016/j.bbrc.2024.151242] [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: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 12/30/2024]
Abstract
Lipid rafts are subdomains of the cell membrane that are rich in cholesterol and glycolipids, and they are involved in various cellular processes and pathophysiological mechanisms. However, the specific role of lipid rafts in hepatocyte dysfunction during the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) is not fully understood. In this study, we investigated the impact of lipid rafts on insulin sensitivity and hepatocyte injury induced by saturated free fatty acids (sFFAs) using primary-cultured mouse hepatocytes. Treatment of primary hepatocytes with palmitic acid (PA) resulted in significant lipid droplet accumulation in the cytoplasm and a marked increase in the number of cells with accumulation of lipid raft. The addition of cholesterol oxidase (CHOX), which disrupts lipid rafts, did not affect PA-induced lipid droplet formation, but significantly reduced the number of cells with accumulation of lipid raft. In PA-treated hepatocytes, insulin-stimulated phosphorylation of insulin receptor substrate (IRS)-2 and Akt was markedly decreased, but this effect was alleviated by CHOX. Furthermore, PA-pretreated hepatocytes exhibited substantial increases in reactive oxygen species (ROS) production and cell death when exposed to low doses of tert-butyl hydroperoxide (t-BuOOH). In contrast, treatment with CHOX after PA significantly reduced ROS production and cell death following t-BuOOH. These results suggest that PA-induced accumulation of lipid raft not only exacerbates insulin resistance but also enhances responsiveness to oxidative stress stimuli, contributing to MASLD pathogenesis. Modulation of lipid rafts may represent a promising therapeutic target for MASLD.
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Affiliation(s)
- Akira Uchiyama
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kazuyoshi Kon
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
| | - Maki Morinaga
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroo Fukada
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Reiko Yaginuma
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kyoko Fukuhara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Shunhei Yamashina
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kazuhisa Iwabuchi
- Graduate School of Health Care and Nursing, Laboratory of Biochemistry, Juntendo University, Chiba, Japan
| | - Kenichi Ikejima
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Yang Y, Wang TT, Xie HA, Hu PP, Li P. Experimental cell models of insulin resistance: overview and appraisal. Front Endocrinol (Lausanne) 2024; 15:1469565. [PMID: 39749015 PMCID: PMC11693592 DOI: 10.3389/fendo.2024.1469565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 12/02/2024] [Indexed: 01/04/2025] Open
Abstract
Insulin resistance, a key factor in the development of type 2 diabetes mellitus (T2DM), is defined as a defect in insulin-mediated control of glucose metabolism in tissues such as liver, fat and muscle. Insulin resistance is a driving force behind various metabolic diseases, such as T2DM, hyperlipidemia, hypertension, coronary heart disease and fatty liver. Therefore, improving insulin sensitivity can be considered as an effective strategy for the prevention and treatment of these complex metabolic diseases. Cell-based models are extensively employed for the study of pathological mechanisms and drug screening, particularly in relation to insulin resistance in T2DM. Currently, numerous methods are available for the establishment of in vitro insulin resistance models, a comprehensive review of these models is required and can serve as an excellent introduction or understanding for researchers undertaking studies in this filed. This review examines and discusses the primary methods for establishing and evaluating insulin resistance cell models. Furthermore, it highlights key issues and suggestions on cell selection, establishment, evaluation and drug screening of insulin resistance, thereby providing valuable references for the future research efforts.
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Affiliation(s)
- Ying Yang
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
| | - Ting-ting Wang
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
| | - Hu-ai Xie
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
| | - Ping Ping Hu
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
| | - Pan Li
- College of Pharmacy, Chongqing Medical University, Chongqing, China
- Chongqing Key Research Laboratory for Drug Metabolism, Chongqing Medical University, Chongqing, China
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Tao Y, Chen Y, Ren J, Jiang S, Zhang S, Xu H, Li Y. Lipidomics and transcriptomics analysis revealed the role of the spleen of Nile tilapia (Oreochromis niloticus) in lipid metabolism. AQUACULTURE 2024; 592:741173. [DOI: 10.1016/j.aquaculture.2024.741173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Garcia-Mateo S, Rondinella D, Ponziani FR, Miele L, Gasbarrini A, Cammarota G, Lanas Á, Gomollón F. Gut microbiome and metabolic dysfunction-associated steatotic liver disease: Pathogenic role and potential for therapeutics. Best Pract Res Clin Gastroenterol 2024; 72:101924. [PMID: 39645278 DOI: 10.1016/j.bpg.2024.101924] [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: 04/06/2024] [Accepted: 05/02/2024] [Indexed: 12/09/2024]
Abstract
Gut microbiota plays key functions in the human body, and its alteration is associated with several human disorders. Moreover, its manipulation is being investigated as a potential therapeutic strategy. In this narrative review we will dissect the involvement of the gut microbiota and of the gut-liver axis on metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, we will review the effects of lifestyle interventions commonly used for MASLD (i.e. Mediterranean diet and physical exercise) on gut microbiome, to understand if their beneficial effect can be microbially mediated. Finally, we will discuss the role and the available evidence of therapeutic microbiome modulators, including prebiotics, probiotics, symbiotics, and fecal microbiota transplantation (FMT), in the management of MASLD.
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Affiliation(s)
- Sandra Garcia-Mateo
- Department of Gastroenterology, "Lozano Blesa" Clinical Hospital, 50009, Zaragoza, Spain; Aragón Health Research Institute (IIS Aragón), 50009, Zaragoza, Spain; School of Medicine, University of Zaragoza, 50009, Zaragoza, Spain.
| | - Debora Rondinella
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Francesca Romana Ponziani
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Luca Miele
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Giovanni Cammarota
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Ángel Lanas
- Department of Gastroenterology, "Lozano Blesa" Clinical Hospital, 50009, Zaragoza, Spain; Aragón Health Research Institute (IIS Aragón), 50009, Zaragoza, Spain; School of Medicine, University of Zaragoza, 50009, Zaragoza, Spain
| | - Fernando Gomollón
- Department of Gastroenterology, "Lozano Blesa" Clinical Hospital, 50009, Zaragoza, Spain; Aragón Health Research Institute (IIS Aragón), 50009, Zaragoza, Spain; School of Medicine, University of Zaragoza, 50009, Zaragoza, Spain
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10
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Zhang JF, Cai FQ, Zhang XC, Ye Q. Monocyte to High-density Lipoprotein Cholesterol Ratio as a Predictor of Nonalcoholic Fatty Liver Disease in Childhood Obesity. Curr Med Sci 2024; 44:692-697. [PMID: 39096480 DOI: 10.1007/s11596-024-2919-6] [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: 06/01/2023] [Accepted: 07/09/2024] [Indexed: 08/05/2024]
Abstract
OBJECTIVE Inflammation is involved in the development and progression of nonalcoholic fatty liver disease (NAFLD). The monocyte to high-density lipoprotein cholesterol ratio (MHR) has emerged as a marker for various inflammation-related diseases. The aim of the present study was to investigate the association between the MHR and NAFLD in a population with childhood obesity. METHODS Based on hepatic ultrasound, a total of 504 children with obesity (357 with NAFLD and 147 without NAFLD) were included in the study. The correlation between the MHR and NAFLD risk factors was assessed by Pearson's and Spearman's analyses. Multivariate stepwise logistic regression analyses were conducted to explore the association between the MHR and the risk of NAFLD. RESULTS The MHR in patients with NAFLD was significantly greater than that in patients without NAFLD [0.52 (0.44-0.67) versus 0.44 (0.34-0.57), P<0.001]. Multivariate stepwise logistic regression analysis demonstrated that the MHR [odds ratio (OR): 1.033, 95% confidence interval (CI): 1.015-1.051; P<0.001] was an independent predictor of NAFLD in childhood obesity patients, as were age (OR: 1.205, 95% CI: 1.059-1.371; P=0.005], waist circumference [OR: 1.037, 95% CI: 1.008-1.067; P=0.012], and alanine transaminase [OR: 1.067, 95% CI: 1.045-1.089; P<0.001]. Additionally, MHR quartiles showed a significant positive association with the incidence of NAFLD after adjusting for potential confounding factors. CONCLUSION The present study showed that the MHR may serve as an available and useful indicator of NAFLD in individuals with childhood obesity.
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Affiliation(s)
- Jun-Feng Zhang
- Department of Laboratory Medicine, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China
| | - Feng-Qing Cai
- Department of Laboratory Medicine, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China
| | - Xiu-Cai Zhang
- Department of Laboratory Medicine, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China
| | - Qing Ye
- Department of Laboratory Medicine, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China.
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11
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Xiao JL, Liu HY, Sun CC, Tang CF. Regulation of Keap1-Nrf2 signaling in health and diseases. Mol Biol Rep 2024; 51:809. [PMID: 39001962 DOI: 10.1007/s11033-024-09771-4] [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: 05/20/2024] [Accepted: 07/01/2024] [Indexed: 07/15/2024]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) functions as a central regulator in modulating the activities of diverse antioxidant enzymes, maintaining cellular redox balance, and responding to oxidative stress (OS). Kelch-like ECH-associated protein 1 (Keap1) serves as a principal negative modulator in controlling the expression of detoxification and antioxidant genes. It is widely accepted that OS plays a pivotal role in the pathogenesis of various diseases. When OS occurs, leading to inflammatory infiltration of neutrophils, increased secretion of proteases, and the generation of large quantities of reactive oxygen radicals (ROS). These ROS can oxidize or disrupt DNA, lipids, and proteins either directly or indirectly. They also cause gene mutations, lipid peroxidation, and protein denaturation, all of which can result in disease. The Keap1-Nrf2 signaling pathway regulates the balance between oxidants and antioxidants in vivo, maintains the stability of the intracellular environment, and promotes cell growth and repair. However, the antioxidant properties of the Keap1-Nrf2 signaling pathway are reduced in disease. This review overviews the mechanisms of OS generation, the biological properties of Keap1-Nrf2, and the regulatory role of its pathway in health and disease, to explore therapeutic strategies for the Keap1-Nrf2 signaling pathway in different diseases.
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Affiliation(s)
- Jiang-Ling Xiao
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of the Hunan Province, College of Physical Education, Hunan Normal University, Changsha, Hunan, 410012, China
| | - Heng-Yuan Liu
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of the Hunan Province, College of Physical Education, Hunan Normal University, Changsha, Hunan, 410012, China
| | - Chen-Chen Sun
- Institute of Physical Education, Hunan First Normal University, Changsha, Hunan, 410205, China.
| | - Chang-Fa Tang
- Key Laboratory of Physical Fitness and Exercise Rehabilitation of the Hunan Province, College of Physical Education, Hunan Normal University, Changsha, Hunan, 410012, China.
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Ahmed M, Ahmed MH. Ramadan Fasting in Individuals with Metabolic Dysfunction-Associated Steatotic Liver Disease, Liver Transplant, and Bariatric Surgery: A Narrative Review. J Clin Med 2024; 13:3893. [PMID: 38999457 PMCID: PMC11242100 DOI: 10.3390/jcm13133893] [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: 05/22/2024] [Revised: 06/25/2024] [Accepted: 07/01/2024] [Indexed: 07/14/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease is a growing worldwide pandemic. A limited number of studies have investigated the potential effect of Ramadan fasting on metabolic dysfunction-associated steatotic liver disease (MASLD). There is no single medication for the treatment of MASLD. There is a growing interest in dietary intervention as potential treatment for metabolic diseases including MASLD. The aim of this study was to discuss the epidemiology, pathogenesis, and risk factors of MASLD and the potential effects of Ramadan fasting on MASLD, liver transplant, and bariatric surgery. We searched PubMed and SCOPUS databases using different search terms. The literature search was based on research studies published in English from the year 2000 to the 2024. Thirty-two studies were included in this review. Ramadan fasting reduced body weight and improved lipid profile, anthropometric indices, fasting plasma glucose, plasma insulin, and inflammatory cytokines. Ramadan fasting improved risk factors of nonalcoholic fatty liver disease and might improve MASLD through weight reduction. However, further studies are needed to assess the safety and effectiveness of Ramadan fasting in liver transplant recipients and bariatric surgery.
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Affiliation(s)
- Musaab Ahmed
- College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Mohamed H Ahmed
- Department of Medicine and HIV Metabolic Clinic, Milton Keynes University Hospital NHS Foundation Trust, Eagelstone, Milton Keynes MK6 5LD, UK
- Department of Geriatric Medicine, Milton Keynes University Hospital NHS Foundation Trust, Eagelstone, Milton Keynes MK6 5LD, UK
- Honorary Senior Lecturer of the Faculty of Medicine and Health Sciences, University of Buckingham, Buckingham MK18 1EG, UK
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Souza-Tavares H, Santana-Oliveira DA, Vasques-Monteiro IML, Silva-Veiga FM, Mandarim-de-Lacerda CA, Souza-Mello V. Exercise enhances hepatic mitochondrial structure and function while preventing endoplasmic reticulum stress and metabolic dysfunction-associated steatotic liver disease in mice fed a high-fat diet. Nutr Res 2024; 126:180-192. [PMID: 38759501 DOI: 10.1016/j.nutres.2024.04.002] [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: 02/01/2024] [Revised: 04/15/2024] [Accepted: 04/15/2024] [Indexed: 05/19/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has attracted increasing attention from the scientific community because of its severe but silent progression and the lack of specific treatment. Glucolipotoxicity triggers endoplasmic reticulum (ER) stress with decreased beta-oxidation and enhanced lipogenesis, promoting the onset of MASLD, whereas regular physical exercise can prevent MASLD by preserving ER and mitochondrial function. Thus, the hypothesis of this study was that high-intensity interval training (HIIT) could prevent the development of MASLD in high-fat (HF)-fed C57BL/6J mice by maintaining insulin sensitivity, preventing ER stress, and promoting beta-oxidation. Forty male C57BL/6J mice (3 months old) comprised 4 experimental groups: the control (C) diet group, the C diet + HIIT (C-HIIT) group, the HF diet group, and the HF diet + HIIT (HF-HIIT) group. HIIT sessions lasted 12 minutes and were performed 3 times weekly by trained mice. The diet and exercise protocols lasted for 10 weeks. The HIIT protocol prevented weight gain and maintained insulin sensitivity in the HF-HIIT group. A chronic HF diet increased ER stress-related gene and protein expression, but HIIT helped to maintain ER homeostasis, preserve mitochondrial ultrastructure, and maximize beta-oxidation. The increased sirtuin-1/peroxisome proliferator-activated receptor-gamma coactivator 1-alpha expression implies that HIIT enhanced mitochondrial biogenesis and yielded adequate mitochondrial dynamics. High hepatic fibronectin type III domain containing 5/irisin agreed with the antilipogenic and anti-inflammatory effects observed in the HF-HIIT group, reinforcing the antisteatotic effects of HIIT. Thus, we confirmed that practicing HIIT 3 times per week maintained insulin sensitivity, prevented ER stress, and enhanced hepatic beta-oxidation, impeding MASLD development in this mouse model even when consuming high energy intake from saturated fatty acids.
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Affiliation(s)
- Henrique Souza-Tavares
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Daiana Araujo Santana-Oliveira
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Isabela Macedo Lopes Vasques-Monteiro
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Flavia Maria Silva-Veiga
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Carlos Alberto Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Vanessa Souza-Mello
- Laboratory of Morphometry, Metabolism and Cardiovascular Diseases, Biomedical Center, Institute of Biology. Rio de Janeiro State University, Rio de Janeiro, Brazil.
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Balejko EB, Bogacka A, Lichota J, Pawlus J. Effects of Bioactive Dietary Components on Changes in Lipid and Liver Parameters in Women after Bariatric Surgery and Procedures. Nutrients 2024; 16:1379. [PMID: 38732625 PMCID: PMC11085392 DOI: 10.3390/nu16091379] [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: 03/11/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Excess adipose tissue, as well as its distribution, correlates strongly with disorders of lipid and liver parameters and chronic inflammation. The pathophysiology of metabolic diseases caused by obesity is associated with the dysfunction of visceral adipose tissue. Effective and alternative interventions such as the Bioenteric Intragastric Balloon and bariatric surgeries such as the Roux-en-Y gastric bypass. The aim of this study was to assess the effect of modifying the recommended standard weight loss diet after bariatric surgery and procedures on reducing chronic inflammation in overweight patients. In the study, bioactive anti-inflammatory dietary components were used supportively. Changes in the concentrations of lipid parameters, liver parameters, antioxidant enzymes, cytokines, and chemokines were demonstrated. The enrichment of the diet, after bariatric surgery, with the addition of n-3 EFAs(Essential Fatty Acids), bioflavonoids, vitamins, and synbiotics resulted in higher weight losses in the patients in the study with a simultaneous reduction in parameters indicating liver dysfunction.
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Affiliation(s)
- Edyta Barbara Balejko
- Department of Commodity Science, Quality Assessment, Process Engineering and Human Nutrition, West Pomeranian University of Technology in Szczecin, 71-459 Szczecin, Poland
| | - Anna Bogacka
- Department of Commodity Science, Quality Assessment, Process Engineering and Human Nutrition, West Pomeranian University of Technology in Szczecin, 71-459 Szczecin, Poland
| | - Jarosław Lichota
- Unii Lubelskiej 1, Department of General, Minimally Invasive and Gastroenterological Surgery, Independent Public Clinical Hospital No. 1 of Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
| | - Jan Pawlus
- Unii Lubelskiej 1, Department of General, Minimally Invasive and Gastroenterological Surgery, Independent Public Clinical Hospital No. 1 of Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland
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15
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Ishay Y, Neutel J, Kolben Y, Gelman R, Arbib OS, Lopez O, Katchman H, Mohseni R, Kidron M, Ilan Y. Oral Insulin Alleviates Liver Fibrosis and Reduces Liver Steatosis in Patients With Metabolic Dysfunction-associated Steatohepatitis and Type 2 Diabetes: Results of Phase II Randomized, Placebo-controlled Feasibility Clinical Trial. GASTRO HEP ADVANCES 2023; 3:417-425. [PMID: 39131144 PMCID: PMC11308786 DOI: 10.1016/j.gastha.2023.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 11/30/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Metabolic dysfunction-associated steatohepatitis is an advanced form of nonalcoholic fatty liver disease and a leading cause of end-stage liver disease and transplantation. Insulin resistance and inflammation underlie the pathogenesis of the disease. Methods This double-blind, randomized, placebo-controlled, multicenter feasibility clinical trial aimed to determine the safety of oral 8 mg insulin in patients with metabolic dysfunction-associated steatohepatitis and type 2 diabetes mellitus. Patients were treated twice daily for 12 weeks with an 8 mg insulin (n = 21) or placebo (n = 11) capsule. Safety was monitored throughout the study. MRI-proton density fat fraction assessed liver fat content, and Fibroscan® measured liver fibrosis and steatosis levels at screening and after 12 weeks of treatment. Results No severe drug-related adverse events were reported during the study. After 12 weeks of treatment, mean percent reductions in whole-liver (-11.2% vs -6.5%, respectively) and liver segment 3 (-11.7% vs +0.1%, respectively) fat content was higher in the insulin than in the placebo arm. Patients receiving insulin showed a median -1.2 kPa and -21.0 dB/m reduction from baseline fibrosis and steatosis levels, respectively, while placebo-treated patients showed median increases of 0.3 kPa and 13.0 dB/m, respectively. At Week 12, oral insulin was associated with a mean of 0.27% reduction and placebo with a 0.23% increase from baseline hemoglobin A1c levels. Mean percent changes from baseline alanine aminotransferase, and aspartate aminotransferase levels were -10% and -0.8%, respectively, in the oral insulin and 3.0% and 13.4%, in the placebo arm. Conclusion The results of this feasibility study support the safety and potential therapeutic effect of orally delivered insulin on liver fibrosis, fat accumulation, and inflammatory processes (NIH Clinical Trials No. NCT04618744).
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Affiliation(s)
- Yuval Ishay
- Department of Medicine, Hadassah Medical Center and Faculty of Medicine Hebrew University, Jerusalem, Israel
| | - Joel Neutel
- Orange County Research Center, Tustin, California
| | - Yotam Kolben
- Department of Medicine, Hadassah Medical Center and Faculty of Medicine Hebrew University, Jerusalem, Israel
| | - Ram Gelman
- Department of Medicine, Hadassah Medical Center and Faculty of Medicine Hebrew University, Jerusalem, Israel
| | - Orly Sneh Arbib
- Department of Medicine, Hadassah Medical Center and Faculty of Medicine Hebrew University, Jerusalem, Israel
| | | | | | | | | | - Yaron Ilan
- Department of Medicine, Hadassah Medical Center and Faculty of Medicine Hebrew University, Jerusalem, Israel
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La Colla A, Cámara CA, Campisano S, Chisari AN. Mitochondrial dysfunction and epigenetics underlying the link between early-life nutrition and non-alcoholic fatty liver disease. Nutr Res Rev 2023; 36:281-294. [PMID: 35067233 DOI: 10.1017/s0954422422000038] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Early-life malnutrition plays a critical role in foetal development and predisposes to metabolic diseases later in life, according to the concept of 'developmental programming'. Different types of early nutritional imbalance, including undernutrition, overnutrition and micronutrient deficiency, have been related to long-term metabolic disorders. Accumulating evidence has demonstrated that disturbances in nutrition during the period of preconception, pregnancy and primary infancy can affect mitochondrial function and epigenetic mechanisms. Moreover, even though multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) have been described, in the past years, special attention has been given to mitochondrial dysfunction and epigenetic alterations. Mitochondria play a key role in cellular metabolic functions. Dysfunctional mitochondria contribute to oxidative stress, insulin resistance and inflammation. Epigenetic mechanisms have been related to alterations in genes involved in lipid metabolism, fibrogenesis, inflammation and tumorigenesis. In accordance, studies have reported that mitochondrial dysfunction and epigenetics linked to early-life nutrition can be important contributing factors in the pathogenesis of NAFLD. In this review, we summarise the current understanding of the interplay between mitochondrial dysfunction, epigenetics and nutrition during early life, which is relevant to developmental programming of NAFLD.
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Affiliation(s)
- Anabela La Colla
- Departamento de Química y Bioquímica, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina
| | - Carolina Anahí Cámara
- Departamento de Química y Bioquímica, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina
| | - Sabrina Campisano
- Departamento de Química y Bioquímica, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina
| | - Andrea Nancy Chisari
- Departamento de Química y Bioquímica, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata, 7600 Mar del Plata, Argentina
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Mastoridou EM, Goussia AC, Kanavaros P, Charchanti AV. Involvement of Lipophagy and Chaperone-Mediated Autophagy in the Pathogenesis of Non-Alcoholic Fatty Liver Disease by Regulation of Lipid Droplets. Int J Mol Sci 2023; 24:15891. [PMID: 37958873 PMCID: PMC10649352 DOI: 10.3390/ijms242115891] [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: 10/09/2023] [Revised: 10/30/2023] [Accepted: 10/30/2023] [Indexed: 11/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of lipids in the form of lipid droplets in more than 5% of hepatocytes. It is regarded as a range of diverse pathologies, including simple steatosis and steatohepatitis. The structural characteristics of lipid droplets, along with their protein composition, mainly including perilipins, have been implicated in the etiology of the disease. These proteins have garnered increasing attention as a pivotal regulator since their levels and distinct expression appear to be associated with the progression from simple steatosis to steatohepatitis. Perilipins are target proteins of chaperone-mediated autophagy, and their degradation is a prerequisite for lipolysis and lipophagy to access the lipid core. Both lipophagy and chaperone-mediated autophagy have significant implications on the development of the disease, as evidenced by their upregulation during the initial phases of simple steatosis and their subsequent downregulation once steatosis is established. On the contrary, during steatohepatitis, the process of chaperone-mediated autophagy is enhanced, although lipophagy remains suppressed. Evidently, the reduced levels of autophagic pathways observed in simple steatosis serve as a defensive mechanism against lipotoxicity. Conversely, in steatohepatitis, chaperone-mediated autophagy fails to compensate for the continuous generation of small lipid droplets and thus cannot protect hepatocytes from lipotoxicity.
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Affiliation(s)
- Eleftheria M. Mastoridou
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; (E.M.M.); (P.K.)
| | - Anna C. Goussia
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece;
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; (E.M.M.); (P.K.)
| | - Antonia V. Charchanti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece; (E.M.M.); (P.K.)
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18
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Atorrasagasti C, Onorato AM, Mazzolini G. The role of SPARC (secreted protein acidic and rich in cysteine) in the pathogenesis of obesity, type 2 diabetes, and non-alcoholic fatty liver disease. J Physiol Biochem 2023; 79:815-831. [PMID: 36018492 DOI: 10.1007/s13105-022-00913-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 07/18/2022] [Indexed: 11/28/2022]
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix glycoprotein with pleiotropic functions, which is expressed in adipose, hepatic, muscular, and pancreatic tissue. Particularly, several studies demonstrated that SPARC is an important player in the context of obesity, diabetes, and fatty liver disease including advanced hepatic fibrosis and hepatocellular carcinoma. Evidence in murine and human samples indicates that SPARC is involved in adipogenesis, cellular metabolism, extracellular matrix modulation, glucose and lipid metabolism, among others. Furthermore, studies in SPARC knockout mouse model showed that SPARC contributes to adipose tissue formation, non-alcoholic fatty liver disease (NAFLD), and diabetes. Hence, SPARC may represent a novel and interesting target protein for future therapeutic interventions or a biomarker of disease progression. This review summarizes the role of SPARC in the pathophysiology of obesity, and extensively revised SPARC functions in physiological and pathological adipose tissue deposition, muscle metabolism, liver, and diabetes-related pathways.
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Affiliation(s)
- Catalina Atorrasagasti
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Instituto de Investigaciones en Medicina Traslacional, CONICET- Universidad Austral, Av. Pte. Perón 1500 (B1629AHJ) Derqui-Pilar, Buenos Aires, Argentina.
| | - Agostina M Onorato
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Instituto de Investigaciones en Medicina Traslacional, CONICET- Universidad Austral, Av. Pte. Perón 1500 (B1629AHJ) Derqui-Pilar, Buenos Aires, Argentina
| | - Guillermo Mazzolini
- Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Instituto de Investigaciones en Medicina Traslacional, CONICET- Universidad Austral, Av. Pte. Perón 1500 (B1629AHJ) Derqui-Pilar, Buenos Aires, Argentina.
- Liver Unit, Hospital Universitario Austral, Universidad Austral, Av. Pte. Perón 1500 (B1629AHJ) Derqui-Pilar, Buenos Aires, Argentina.
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Zheng Y, Wang S, Wu J, Wang Y. Mitochondrial metabolic dysfunction and non-alcoholic fatty liver disease: new insights from pathogenic mechanisms to clinically targeted therapy. J Transl Med 2023; 21:510. [PMID: 37507803 PMCID: PMC10375703 DOI: 10.1186/s12967-023-04367-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is among the most widespread metabolic disease globally, and its associated complications including insulin resistance and diabetes have become threatening conditions for human health. Previous studies on non-alcoholic fatty liver disease (NAFLD) were focused on the liver's lipid metabolism. However, growing evidence suggests that mitochondrial metabolism is involved in the pathogenesis of NAFLD to varying degrees in several ways, for instance in cellular division, oxidative stress, autophagy, and mitochondrial quality control. Ultimately, liver function gradually declines as a result of mitochondrial dysfunction. The liver is unable to transfer the excess lipid droplets outside the liver. Therefore, how to regulate hepatic mitochondrial function to treat NAFLD has become the focus of current research. This review provides details about the intrinsic link of NAFLD with mitochondrial metabolism and the mechanisms by which mitochondrial dysfunctions contribute to NAFLD progression. Given the crucial role of mitochondrial metabolism in NAFLD progression, the application potential of multiple mitochondrial function improvement modalities (including physical exercise, diabetic medications, small molecule agonists targeting Sirt3, and mitochondria-specific antioxidants) in the treatment of NAFLD was evaluated hoping to provide new insights into NAFLD treatment.
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Affiliation(s)
- Youwei Zheng
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Shiting Wang
- Department of Cardiovascular Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Jialiang Wu
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Yong Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
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20
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Ramakrishnan S, Mooli RGR, Han Y, Fiorenza E, Kumar S, Bello F, Nallanagulagari A, Karra S, Teng L, Jurczak M. Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning. RESEARCH SQUARE 2023:rs.3.rs-3147009. [PMID: 37503004 PMCID: PMC10371136 DOI: 10.21203/rs.3.rs-3147009/v1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Liver-derived ketone bodies play a crucial role in fasting energy homeostasis by fueling the brain and peripheral tissues. Ketogenesis also acts as a conduit to remove excess acetyl-CoA generated from fatty acid oxidation and protects against diet-induced hepatic steatosis. Surprisingly, no study has examined the role of ketogenesis in fasting-associated hepatocellular lipid metabolism. Ketogenesis is driven by the rate-limiting mitochondrial enzyme 3-hydroxymethylglutaryl CoA synthase (HMGCS2) abundantly expressed in the liver. Here, we show that ketogenic insufficiency via disruption of hepatic HMGCS2 exacerbates liver steatosis in fasted chow and high-fat-fed mice. We found that the hepatic steatosis is driven by increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification via acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, acetyl-CoA accumulation from impaired hepatic ketogenesis is responsible for the elevated translocation of ACSL1 to the ER. Moreover, we show increased ER-localized ACSL1 and re-esterification of lipids in human NASH displaying impaired hepatic ketogenesis. Finally, we show that L-carnitine, which buffers excess acetyl-CoA, decreases the ER-associated ACSL1 and alleviates hepatic steatosis. Thus, ketogenesis via controlling hepatocellular acetyl-CoA homeostasis regulates lipid partitioning and protects against hepatic steatosis.
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21
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Morales-Ferra DL, Zavala-Sánchez MÁ, Jiménez-Ferrer E, Trejo-Moreno C, González-Cortazar M, Gamboa-Gómez CI, Guerrero-Romero F, Zamilpa A. Chemical Characterization, Antilipidemic Effect and Anti-Obesity Activity of Ludwigia octovalvis in a Murine Model of Metabolic Syndrome. PLANTS (BASEL, SWITZERLAND) 2023; 12:2578. [PMID: 37447139 DOI: 10.3390/plants12132578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/02/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023]
Abstract
Ludwigia octovalvis (Jacq.) P.H. Raven is widely used in traditional medicine for different illnesses, including diabetes and hypertension. However, its impact on lipotoxicity and metabolic syndrome in vivo has not been addressed. Therefore, the aim of this study was to evaluate the effects of this plant on the metabolic syndrome parameters in a C57BL6J mouse hypercaloric diet model. L. octovalvis hydroalcoholic extract and its ethyl acetate fraction (25 mg/kg/day) were used for sub-chronic assessment (10 weeks). Additionally, four subfractions (25 mg/kg) were evaluated in the postprandial triglyceridemia test in healthy C57BL6J mice. The hydroalcoholic extract and ethyl acetate fraction significantly decreased body weight gain (-6.9 g and -1.5 g), fasting glycemia (-46.1 and -31.2 mg/dL), systolic (-26.0 and -22.5 mmHg) and diastolic (-8.1 and 16.2 mmHg) blood pressure, free fatty acid concentration (-13.8 and -8.0 μg/mL) and insulin-resistance (measured by TyG index, -0.207 and -0.18), compared to the negative control. A postprandial triglyceridemia test showed that the effects in the sub-chronic model are due, at least in part, to improvement in this parameter. L. octovalvis treatments, particularly the hydroalcoholic extract, improve MS alterations and decrease free fatty acid concentration. These effects are possibly due to high contents of corilagin and ellagic acid.
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Affiliation(s)
- Dulce Lourdes Morales-Ferra
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Xochitepec 62790, Mexico
- Doctorado en Ciencias Biológicas y de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana (UAM), Mexico City 04960, Mexico
| | - Miguel Ángel Zavala-Sánchez
- Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana (UAM), Mexico City 04960, Mexico
| | - Enrique Jiménez-Ferrer
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Xochitepec 62790, Mexico
| | - Celeste Trejo-Moreno
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca 62350, Mexico
| | - Manasés González-Cortazar
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Xochitepec 62790, Mexico
| | - Claudia I Gamboa-Gómez
- Unidad de Investigación Biomédica, Instituto Mexicano del Seguro Social, Canoas 100, Durango 34067, Mexico
| | - Fernando Guerrero-Romero
- Unidad de Investigación Biomédica, Instituto Mexicano del Seguro Social, Canoas 100, Durango 34067, Mexico
| | - Alejandro Zamilpa
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Xochitepec 62790, Mexico
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Novi S, Vestuto V, Campiglia P, Tecce N, Bertamino A, Tecce MF. Anti-Angiogenic Effects of Natural Compounds in Diet-Associated Hepatic Inflammation. Nutrients 2023; 15:2748. [PMID: 37375652 DOI: 10.3390/nu15122748] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/09/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common causes of chronic liver disease and are increasingly emerging as a global health problem. Such disorders can lead to liver damage, resulting in the release of pro-inflammatory cytokines and the activation of infiltrating immune cells. These are some of the common features of ALD progression in ASH (alcoholic steatohepatitis) and NAFLD to NASH (non-alcoholic steatohepatitis). Hepatic steatosis, followed by fibrosis, lead to a continuous progression accompanied by angiogenesis. This process creates hypoxia, which activates vascular factors, initiating pathological angiogenesis and further fibrosis. This forms a vicious cycle of ongoing damage and progression. This condition further exacerbates liver injury and may contribute to the development of comorbidities, such as metabolic syndrome as well as hepatocellular carcinoma. Increasing evidence suggests that anti-angiogenic therapy may have beneficial effects on these hepatic disorders and their exacerbation. Therefore, there is a great interest to deepen the knowledge of the molecular mechanisms of natural anti-angiogenic products that could both prevent and control liver diseases. In this review, we focus on the role of major natural anti-angiogenic compounds against steatohepatitis and determine their potential therapeutic benefits in the treatment of liver inflammation caused by an imbalanced diet.
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Affiliation(s)
- Sara Novi
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
| | - Vincenzo Vestuto
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
| | - Pietro Campiglia
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
| | - Nicola Tecce
- Unit of Endocrinology, Department of Clinical Medicine and Surgery, Medical School of Naples, Federico II University, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Alessia Bertamino
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
| | - Mario Felice Tecce
- Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, Italy
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Su P, Chen JG, Tang DH. Exercise against nonalcoholic fatty liver disease: Possible role and mechanism of lipophagy. Life Sci 2023; 327:121837. [PMID: 37301321 DOI: 10.1016/j.lfs.2023.121837] [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: 04/13/2023] [Revised: 05/25/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide. NAFLD is prevalent in about 30% of people worldwide. The lack of physical activity is considered as one of the risks for NAFLD, and approximately one-third of NAFLD patients hardly engage in physical activity. It is acknowledged that exercise is one of the optimal non-pharmacological methods for preventing and treating NAFLD. Different forms of exercise such as aerobic exercise, resistance exercise and even simply physical activity in a higher level can be beneficial in reducing liver lipid accumulation and disease progression for NAFLD patients. In NAFLD patients, exercise is helpful in lowering steatosis and enhancing liver function. The mechanisms underlying the prevention and treatment of NAFLD by exercise are various and complex. Current studies on the mechanisms have focused on the pro-lipolytic, anti-inflammatory, and antioxidant and lipophagy. Promotion of lipophagy is regarded as an important mechanism for prevention and improvement of NAFLD by exercise. Recent studies have investigated the above mechanism, yet the potential mechanism has not been completely elucidated. Thus, in this review, we cover the recent advances of exercise-promoted lipophagy in NAFLD treatment and prevention. Furthermore, given the fact that exercise activates SIRT1, we discuss the possible regulatory mechanisms of lipophagy by SIRT1 during exercise. These mechanisms need to be verified by further experimental studies.
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Affiliation(s)
- Pei Su
- Department of College of P.E. and Sport, Beijing Normal University, No. 19, Xinjiekouwai St, Haidian District, Beijing 100875, People's Republic of China.
| | - Jian-Gang Chen
- Department of College of P.E. and Sport, Beijing Normal University, No. 19, Xinjiekouwai St, Haidian District, Beijing 100875, People's Republic of China.
| | - Dong-Hui Tang
- Department of College of P.E. and Sport, Beijing Normal University, No. 19, Xinjiekouwai St, Haidian District, Beijing 100875, People's Republic of China.
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Béland-Bonenfant S, Petit JM, Vergès B. NAFLD et NASH au cours du diabète : données épidémiologiques, cliniques et pronostiques. MÉDECINE DES MALADIES MÉTABOLIQUES 2023; 17:248-252. [DOI: 10.1016/j.mmm.2023.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Chen N, Wu LJ, Xiao HB, Liu YH, Hu LK, Ma LL, Chu X, Dong J, Yan YX. Occupational stress is associated with insulin resistance and incident type 2 diabetes: a prospective cohort study of functional community. Clin Chim Acta 2023; 544:117356. [PMID: 37094773 DOI: 10.1016/j.cca.2023.117356] [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: 03/03/2023] [Revised: 03/31/2023] [Accepted: 04/14/2023] [Indexed: 04/26/2023]
Abstract
BACKGROUND To exploit the association of occupational stress with the development of insulin resistance (IR) and type 2 diabetes (T2D) in a Chinese population-based cohort. METHODS A total of 6109 participants from a functional community cohort in Beijing were enrolled in 2015 and followed up until 2021. Copenhagen Psychosocial Questionnaire (COPSOQ) were used to evaluate occupational stress. RESULTS At baseline, increase values of all five scales of COPSOQ and total COPSOQ were significantly associated with IR. During an average 5.63 y follow-up, 732 individuals developed T2D. Increasing in values of "Demands at work", "Insecurity at work", "Job satisfaction" and total COPSOQ were significantly associated with incident T2D (P<0.01). Mediation analysis showed that subjectively perceived occupational stress promoted T2D mainly by affecting plasma cortisol and the mediation effects of HOMA-IR, SBP, DBP, TG, Urea and UA were significant on the association between cortisol and incident T2D, with proportion mediated of 37.1%, 8.12%, 2.02%, 2.94%, 2.35% and 2.70%. CONCLUSION Occupational stress was independently associated with the development of IR and T2D. IR, BP, TG, Urea and UA all partly mediated the association between occupational stress and incident T2D.
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Affiliation(s)
- Ning Chen
- Department of Epidemiology and Biostatistics, and Municipal Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Li-Juan Wu
- Department of Epidemiology and Biostatistics, and Municipal Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Huan-Bo Xiao
- Department of Preventive Medicine, Yanjing Medical College, Capital Medical University, Beijing, China
| | - Yu-Hong Liu
- Department of Epidemiology and Biostatistics, and Municipal Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Li-Kun Hu
- Department of Epidemiology and Biostatistics, and Municipal Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Lin-Lin Ma
- Department of Epidemiology and Biostatistics, and Municipal Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Xi Chu
- Health Management Center, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jing Dong
- Health Management Center, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yu-Xiang Yan
- Department of Epidemiology and Biostatistics, and Municipal Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China.
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Nobiletin Intake Attenuates Hepatic Lipid Profiling and Oxidative Stress in HFD-Induced Nonalcoholic-Fatty-Liver-Disease Mice. Molecules 2023; 28:molecules28062570. [PMID: 36985541 PMCID: PMC10054910 DOI: 10.3390/molecules28062570] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023] Open
Abstract
Nobiletin (NOB) is a naturally occurring compound, commonly found in citrus peel, that shows hepatoprotective and lipid-reducing effects. However, the lipid biomarkers and the potential improvement mechanisms have not been adequately explored. Therefore, we investigated the ameliorative effect and the molecular mechanism of NOB on NAFLD induced by a high-fat diet in mice. The results showed that supplementation with NOB over 12 weeks markedly improved glucose tolerance, serum lipid profiles, inflammatory factors, hepatic steatosis, and oxidative stress. These beneficial effects were mainly related to reduced levels of potential lipid biomarkers including free fatty acids, diacylglycerols, triacylglycerols, and cholesteryl esters according to hepatic lipidomic analysis. Twenty lipids, including DGs and phosphatidylcholines, were identified as potential lipid biomarkers. Furthermore, RT-qPCR and Western blot analysis indicated that NOB inhibited the expression of lipogenesis-related factors such as SREBP-1c, SCD-1, and FAS, and upregulated the expression of lipid oxidation (PPARα) and cholesterol conversion (LXRα, CYP7A1, and CYP27A1) genes as well as antioxidation-related factors (Nucl-Nrf2, NQO1, HO-1, and GCLC), indicating that NOB intake may reduce lipid biosynthesis and increase lipid consumption to improve hepatic steatosis and oxidative stress. This study is beneficial for understanding the ameliorative effects of NOB on NAFLD.
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Huang S, Wu B, He Y, Qiu R, Yang T, Wang S, Lei Y, Li H, Zheng F. Canagliflozin ameliorates the development of NAFLD by preventing NLRP3-mediated pyroptosis through FGF21-ERK1/2 pathway. Hepatol Commun 2023; 7:e0045. [PMID: 36757426 PMCID: PMC9916118 DOI: 10.1097/hc9.0000000000000045] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/05/2022] [Indexed: 02/10/2023] Open
Abstract
Recent studies have suggested that sodium-glucose co-transporter2 inhibitors go beyond their glycemic advantages to ameliorate the development of NAFLD. However, little research has been done on the underlying mechanisms. Here, we took deep insight into the effect of canagliflozin (CANA), one of the sodium-glucose co-transporter2 inhibitor, on the progression of NAFLD, and explored the molecular mechanisms. Our findings showed that CANA-treated ob/ob and diabetic mice developed improved glucose and insulin tolerance, although their body weights were comparable or even increased compared with the controls. The CANA treatment ameliorated hepatic steatosis and lipid accumulation of free fatty acid-treated AML12 cells, accompanied by decreased lipogenic gene expression and increased fatty acid β oxidation-related gene expression. Furthermore, inflammation and fibrosis genes decreased in the livers of CANA-treated ob/ob and diabetic mice mice. FGF21 and its downstream ERK1/2/AMPK signaling decreased, whereas NLRP3-mediated pyroptosis increased in the livers of the ob/ob and diabetic mice mice, which was reversed by the CANA treatment. In addition, blocking FGF21 or ERK1/2 activity antagonized the effects of CANA on NLRP3-mediated pyroptosis in lipopolysaccharide plus nigericin-treated J774A.1 cells. We conclude that CANA treatment alleviated insulin resistance and the progression of NAFLD in ob/ob and diabetic mice mice independent of the body weight change. CANA protected against the progression of NAFLD by inhibiting NLRP3-mediated pyroptosis and enhancing FGF21-ERK1/2 pathway activity in the liver. These findings suggest the therapeutic potential of sodium-glucose co-transporter2 inhibitors in the treatment of NAFLD.
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Affiliation(s)
- Shaohan Huang
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Beibei Wu
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yingzi He
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Ruojun Qiu
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Tian Yang
- Department of Endocrinology, The Affiliated Fourth Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Shuo Wang
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Yongzhen Lei
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Hong Li
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Fenping Zheng
- Department of Endocrinology, The Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
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28
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Ji L, Deng H, Xue H, Wang J, Hong K, Gao Y, Kang X, Fan G, Huang W, Zhan J, You Y. Research progress regarding the effect and mechanism of dietary phenolic acids for improving nonalcoholic fatty liver disease via gut microbiota. Compr Rev Food Sci Food Saf 2023; 22:1128-1147. [PMID: 36717374 DOI: 10.1111/1541-4337.13106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 12/16/2022] [Accepted: 12/22/2022] [Indexed: 02/01/2023]
Abstract
Phenolic acids (PAs), a class of small bioactive molecules widely distributed in food and mainly found as secondary plant metabolites, present significant advantages such as antioxidant activity and other health benefits. The global epidemic of nonalcoholic fatty liver disease (NAFLD) is becoming a serious public health problem. Existing studies showed that gut microbiota (GM) dysbiosis is highly associated with the occurrence and development of NAFLD. In recent years, progress has been made in the study of the relationship among PA compounds, GM, and NAFLD. PAs can regulate the composition and functions of the GM to promote human health, while GM can increase the dietary sources of PAs and improve its bioavailability. This paper discussed PAs, GM, and their interrelationship while introducing several representative dietary PA sources and examining the absorption and metabolism of PAs mediated by GM. It also summarizes the effect and mechanisms of PAs in improving and regulating NAFLD via GM and their metabolites. This helps to better evaluate the potential preventive effect of PAs on NAFLD via the regulation of GM and expands the utilization of PAs and PA-rich food resources.
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Affiliation(s)
- Lin Ji
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Huan Deng
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Huimin Xue
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Jiting Wang
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Kexin Hong
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Yunxiao Gao
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Xiping Kang
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Guanghe Fan
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Weidong Huang
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Jicheng Zhan
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
| | - Yilin You
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China
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Concise review of lipidomics in nonalcoholic fatty liver disease. DIABETES & METABOLISM 2023; 49:101432. [PMID: 36781065 DOI: 10.1016/j.diabet.2023.101432] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/23/2023] [Accepted: 02/01/2023] [Indexed: 02/13/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses simple liver steatosis, nonalcoholic steatohepatitis (NASH), and liver fibrosis that can progress to cirrhosis. NAFLD has become the principal cause of chronic liver disease in many parts of the world. Lipidomic studies, by allowing to determine concentrations of lipid classes and fatty acid composition of different lipid species, have been of great interest to help understand NAFLD pathophysiology and potentially identify novel biomarkers for diagnosis and prognosis. Indeed, lipidomic data give information on qualitative lipid abnormalities associated with NAFLD. The aim of our article was to create a comprehensive and more synthetic review of main results from lipidomic studies in NAFLD. Literature was searched for all human lipidomic studies evaluating plasma samples of individuals with NAFLD. Results were regrouped by the degree of liver damage, either simple steatosis, NASH or liver fibrosis, and presented by lipid categories. Overall, we summarized the main lipidomic abnormalities associated with NAFLD as follows: modification of free fatty acid distribution, increase in ceramides, reduced phosphatidylcholine / phosphatidylethanolamine ratio, and increase in eicosanoids. These lipid abnormalities are likely to promote NASH and liver fibrosis by inducing mitochondrial dysfunction, apoptosis, inflammation, oxidation, and endoplasmic reticulum stress. Although these lipidomic abnormalities are consistently reported in many studies, further research is needed to clarify whether they may be predictive for liver steatosis, NASH or liver fibrosis.
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Nguyen Huu T, Park J, Zhang Y, Duong Thanh H, Park I, Choi JM, Yoon HJ, Park SC, Woo HA, Lee SR. The Role of Oxidative Inactivation of Phosphatase PTEN and TCPTP in Fatty Liver Disease. Antioxidants (Basel) 2023; 12:antiox12010120. [PMID: 36670982 PMCID: PMC9854873 DOI: 10.3390/antiox12010120] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are becoming increasingly prevalent worldwide. Despite the different etiologies, their spectra and histological feature are similar, from simple steatosis to more advanced stages such as steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Studies including peroxiredoxin knockout models revealed that oxidative stress is crucial in these diseases, which present as consequences of redox imbalance. Protein tyrosine phosphatases (PTPs) are a superfamily of enzymes that are major targets of reactive oxygen species (ROS) because of an oxidation-susceptible nucleophilic cysteine in their active site. Herein, we review the oxidative inactivation of two tumor suppressor PTPs, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and T-cell protein tyrosine phosphatase (TCPTP), and their contribution to the pathogenicity of ALD and NAFLD, respectively. This review might provide a better understanding of the pathogenic mechanisms of these diseases and help develop new therapeutic strategies to treat fatty liver disease.
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Affiliation(s)
- Thang Nguyen Huu
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun 58 128, Republic of Korea
| | - Jiyoung Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Ying Zhang
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Hien Duong Thanh
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun 58 128, Republic of Korea
- Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Iha Park
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Jin Myung Choi
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Hyun Joong Yoon
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Sang Chul Park
- The Future Life and Society Research Center, Advanced Institute of Aging Science, Chonnam National University, Gwangju 61469, Republic of Korea
| | - Hyun Ae Woo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Seung-Rock Lee
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Correspondence: ; Tel.: +82-61-379-2775; Fax: +82-61-379-2782
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Donath H, Wölke S, Knop V, Heß U, Duecker RP, Trischler J, Poynard T, Schubert R, Zielen S. Liver Assessment in Patients with Ataxia-Telangiectasia: Transient Elastography Detects Early Stages of Steatosis and Fibrosis. Can J Gastroenterol Hepatol 2023; 2023:2877350. [PMID: 36941982 PMCID: PMC10024628 DOI: 10.1155/2023/2877350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 01/12/2023] [Accepted: 01/31/2023] [Indexed: 03/13/2023] Open
Abstract
Background Ataxia-telangiectasia (A-T) is a rare autosomal-recessive multisystem disorder characterized by pronounced cerebellar ataxia, telangiectasia, cancer predisposition, and altered body composition. Liver diseases with steatosis, fibrosis, and hepatocellular carcinoma are frequent findings in older patients but sensitive noninvasive diagnostic tools are lacking. Objectives To determine the sensitivity of transient elastography (TE) as a screening tool for early hepatic tissue changes and serum biomarkers for liver disease. Methods Thirty-one A-T patients aged 2 to 25 years were examined prospectively from 2016-2018 by TE. In addition, we evaluated the diagnostic performance of liver biomarkers for steatosis and necroinflammatory activity (SteatoTest and ActiTest, Biopredictive, Paris) compared to TE. For calculation and comparison, patients were divided into two groups (<12, >12 years of age). Results TE revealed steatosis in 2/21 (10%) younger patients compared to 9/10 (90%) older patients. Fibrosis was present in 3/10 (30%) older patients as assessed by TE. We found a significant correlation of steatosis with SteatoTest, alpha-fetoprotein (AFP), HbA1c, and triglycerides. Liver stiffness correlated significantly with SteatoTest, ActiTest, HbA1c, and triglycerides. Conclusion Liver disease is a common finding in older A-T patients. TE is an objective measure to detect early stages of steatosis and fibrosis. SteatoTest and ActiTest are a good diagnostic assessment for steatosis and necroinflammatory activity in patients with A-T and confirmed the TE results.
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Affiliation(s)
- H. Donath
- 1Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic Fibrosis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - S. Wölke
- 1Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic Fibrosis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - V. Knop
- 2Department of Internal Medicine 1, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - U. Heß
- 1Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic Fibrosis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - R. P. Duecker
- 1Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic Fibrosis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - J. Trischler
- 1Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic Fibrosis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - T. Poynard
- 3Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Hepatology Department, Frankfurt, Germany
| | - R. Schubert
- 1Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic Fibrosis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - S. Zielen
- 1Department for Children and Adolescents, Division of Allergology, Pulmonology and Cystic Fibrosis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
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Li R, Kong D, Ye Z, Zong G, Hu K, Xu W, Fang P, Zhang L, Zhou Y, Zhang K, Xue Y. Correlation of multiple lipid and lipoprotein ratios with nonalcoholic fatty liver disease in patients with newly diagnosed type 2 diabetic mellitus: A retrospective study. Front Endocrinol (Lausanne) 2023; 14:1127134. [PMID: 36875464 PMCID: PMC9982122 DOI: 10.3389/fendo.2023.1127134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/03/2023] [Indexed: 02/19/2023] Open
Abstract
BACKGROUND AND OBJECTIVE The diagnostic value of lipid and lipoprotein ratios for NAFLD in newly diagnosed T2DM remains unclear. This study aimed to investigate the relationships between lipid and lipoprotein ratios and the risk of NAFLD in subjects with newly diagnosed T2DM. METHODS A total of 371 newly diagnosed T2DM patients with NAFLD and 360 newly diagnosed T2DM without NAFLD were enrolled in the study. Demographics variables, clinical history and serum biochemical indicators of the subjects were collected. Six lipid and lipoprotein ratios, including triglycerides to high-density lipoprotein-cholesterol (TG/HDL-C) ratio, cholesterol to HDL-C (TC/HDL-C) ratio, free fatty acid to HDL-C (FFA/HDL-C) ratio, uric acid to HDL-C (UA/HDL-C) ratio, low-density lipoprotein-cholesterol to HDL-C (LDL-C/HDL-C) ratio, apolipoprotein B to apolipoprotein A1 (APOB/A1) ratio, were calculated. We compared the differences in lipid and lipoprotein ratios between NAFLD group and non-NAFLD group, and further analyzed the correlation and diagnostic value of these ratios with the risk of NAFLD in the newly diagnosed T2DM patients. RESULTS The proportion of NAFLD in patients with newly diagnosed T2DM increased progressively over the range Q1 to Q4 of six lipid ratios, including the TG/HDL-C ratio, TC/HDL-C ratio, FFA/HDL-C ratio, UA/HDL-C ratio, LDL-C/HDL-C ratio, and APOB/A1 ratio. After adjusting for multiple confounders, TG/HDL-C, TC/HDL-C, UA/HDL-C, LDL-C/HDL-C and APOB/A1 were all strongly correlated with the risk of NAFLD in patients with newly diagnosed T2DM. In patients with newly-onset T2DM, the TG/HDL-C ratio was the most powerful indicator for the diagnosis of NAFLD among all six indicators, with an area under the curve (AUC) of 0.732 (95% CI 0.696-0.769). In addition, TG/HDL-C ratio>1.405, with a sensitivity of 73.8% and specificity of 60.1%, had a good diagnostic ability for NAFLD in patients with newly diagnosed T2DM. CONCLUSIONS The TG/HDL-C ratio may be an effective marker to help identify the risk of NAFLD in patients with newly diagnosed T2DM.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Ying Xue
- *Correspondence: Ying Xue, ; Keqin Zhang,
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Heintz MM, Eccles JA, Olack EM, Maner-Smith KM, Ortlund EA, Baldwin WS. Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity. PLoS One 2022; 17:e0277053. [PMID: 36520866 PMCID: PMC9754190 DOI: 10.1371/journal.pone.0277053] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/18/2022] [Indexed: 12/23/2022] Open
Abstract
Multiple factors in addition to over consumption lead to obesity and non-alcoholic fatty liver disease (NAFLD) in the United States and worldwide. CYP2B6 is the only human detoxification CYP whose loss is associated with obesity, and Cyp2b-null mice show greater diet-induced obesity with increased steatosis than wildtype mice. However, a putative mechanism has not been determined. LC-MS/MS revealed that CYP2B6 metabolizes PUFAs, with a preference for metabolism of ALA to 9-HOTrE and to a lesser extent 13-HOTrE with a preference for metabolism of PUFAs at the 9- and 13-positions. To further study the role of CYP2B6 in vivo, humanized-CYP2B6-transgenic (hCYP2B6-Tg) and Cyp2b-null mice were fed a 60% high-fat diet for 16 weeks. Compared to Cyp2b-null mice, hCYP2B6-Tg mice showed reduced weight gain and metabolic disease as measured by glucose tolerance tests, however hCYP2B6-Tg male mice showed increased liver triglycerides. Serum and liver oxylipin metabolite concentrations increased in male hCYP2B6-Tg mice, while only serum oxylipins increased in female hCYP2B6-Tg mice with the greatest increases in LA oxylipins metabolized at the 9 and 13-positions. Several of these oxylipins, specifically 9-HODE, 9-HOTrE, and 13-oxoODE, are PPAR agonists. RNA-seq data also demonstrated sexually dimorphic changes in gene expression related to nuclear receptor signaling, especially CAR > PPAR with qPCR suggesting PPARγ signaling is more likely than PPARα signaling in male mice. Overall, our data indicates that CYP2B6 is an anti-obesity enzyme, but probably to a lesser extent than murine Cyp2b's. Therefore, the inhibition of CYP2B6 by xenobiotics or dietary fats can exacerbate obesity and metabolic disease potentially through disrupted PUFA metabolism and the production of key lipid metabolites.
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Affiliation(s)
- Melissa M. Heintz
- Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
| | - Jazmine A. Eccles
- Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
| | - Emily M. Olack
- Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
| | - Kristal M. Maner-Smith
- Emory Integrated Metabolomics and Lipodomics Core, Emory University, Atlanta, Georgia, United States of America
| | - Eric A. Ortlund
- Department of Biochemistry, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States of America
| | - William S. Baldwin
- Biological Sciences, Clemson University, Clemson, South Carolina, United States of America
- * E-mail:
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The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network. Cancers (Basel) 2022; 14:cancers14246151. [PMID: 36551635 PMCID: PMC9776867 DOI: 10.3390/cancers14246151] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/06/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.
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Chua D, Low ZS, Cheam GX, Ng AS, Tan NS. Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm. Int J Mol Sci 2022; 23:14762. [PMID: 36499091 PMCID: PMC9737809 DOI: 10.3390/ijms232314762] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/15/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Fatty liver disease is an emerging contributor to disease burden worldwide. The past decades of work established the heterogeneous nature of non-alcoholic fatty liver disease (NAFLD) etiology and systemic contributions to the pathogenesis of the disease. This called for the proposal of a redefinition in 2020 to that of metabolic dysfunction-associated fatty liver disease (MAFLD) to better reflect the current understanding of the disease. To date, several clinical cohort studies comparing NAFLD and MAFLD hint at the relevancy of the new nomenclature in enriching for patients with more severe hepatic injury and extrahepatic comorbidities. However, the underlying systemic pathogenesis is still not fully understood. Preclinical animal models have been imperative in elucidating key biological mechanisms in various contexts, including intrahepatic disease progression, interorgan crosstalk and systemic dysregulation. Furthermore, they are integral in developing novel therapeutics against MAFLD. However, substantial contextual variabilities exist across different models due to the lack of standardization in several aspects. As such, it is crucial to understand the strengths and weaknesses of existing models to better align them to the human condition. In this review, we consolidate the implications arising from the change in nomenclature and summarize MAFLD pathogenesis. Subsequently, we provide an updated evaluation of existing MAFLD preclinical models in alignment with the new definitions and perspectives to improve their translational relevance.
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Affiliation(s)
- Damien Chua
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore
| | - Zun Siong Low
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore
| | - Guo Xiang Cheam
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Aik Seng Ng
- Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore
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Melander SA, Katri A, Karsdal MA, Henriksen K. Improved metabolic efficacy of a dual amylin and calcitonin receptor agonist when combined with semaglutide or empagliflozin. Eur J Pharmacol 2022; 938:175397. [PMID: 36414113 DOI: 10.1016/j.ejphar.2022.175397] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 11/15/2022] [Accepted: 11/15/2022] [Indexed: 11/21/2022]
Abstract
Pharmacotherapies for obesity and type 2 diabetes (T2D) are thought to bridge the gap between lifestyle modification and the weight loss obtained with bariatric surgery. Although the effect of monotherapies, namely amylin and glucagon-like peptide-1 receptor (GLP-1R) agonists, has shown great potential, combination therapy is now becoming a strategy to optimize efficacy for weight management while minimizing adverse effects. This study investigated a dual amylin and calcitonin receptor agonist (DACRA); KBP-066A in combination with the GLP-1R agonist semaglutide or the sodium-glucose co transporter-2 inhibitor (SGLT2i) empagliflozin for anti-obesity and anti-diabetic treatment. The effect of KBP-066A, semaglutide, and empagliflozin alone and in combination was studied with respect to their impact on body weight, food intake, and glucose metabolism in high-fat diet (HFD) and Zucker diabetic fatty (fa/fa) (ZDF) rats. Treatment with KBP-066A and semaglutide lowered body weight by 13% and 9.7%. In contrast, a combination of both KBP-066A + semaglutide reduced body weight by 21% in HFD rats demonstrating superiority compared to monotherapies alone. A combination of KBP-066A with semaglutide or empagliflozin significantly lowered fasting blood glucose, and HbA1C (%) levels in ZDF rats. The complementary action by KBP-066A to GLP-1R agonist and SGLT2i on BW, food intake and glucose control endorsed the potential of DACRAs as an add-on therapy to therapeutic options for T2D and obesity.
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Affiliation(s)
| | - Anna Katri
- Nordic Bioscience, 2730, Herlev, Denmark
| | - Morten A Karsdal
- Nordic Bioscience, 2730, Herlev, Denmark; KeyBioscience AG, Stans, Switzerland
| | - Kim Henriksen
- Nordic Bioscience, 2730, Herlev, Denmark; KeyBioscience AG, Stans, Switzerland
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Zhao Y, Zhao W, Wang H, Zhao Y, Bu H, Takahashi H. Pioglitazone on nonalcoholic steatohepatitis: A systematic review and meta-analysis of 15 RCTs. Medicine (Baltimore) 2022; 101:e31508. [PMID: 36401449 PMCID: PMC9678615 DOI: 10.1097/md.0000000000031508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis is regarded as a risk factor of many liver diseases. METHODS Relevant studies were searched from The National Library of Medicine, Cochrane Library, Elsevier, China National Knowledge Infrastructure, Web of Science and WANFANG databases. A total of 15 eligible studies were analyzed in the Reviewer Manager 5.3 software, including 7 English articles and 8 Chinese articles. RESULTS Fifteen studies are selected for this meta-analysis, which includes totally 623 patients in the treatment group and 594 patients in the control group. As a result, 8 studies show that the total effective rate of the treatment group is higher than that of the control group [Z = 3.64, 95% confidence intervals (CI): 1.78 (1.31-2.43), P = .0003]; eleven studies show that fasting plasma glucose levels of the experimental group are lower than that of the control group [Z = 4.38, 95% CI: -0.95 (-1.38 to -0.53), P < .0001]; ten studies show that glutamic-pyruvic transaminase levels of the experimental group are lower than that of the control group [Z = 3.69, 95% CI: -11.76 (-18.01 to -5.51), P = .0002]; 6 studies show that glutamic oxalacetic transaminase levels of the experimental group are lower than that of the control group [Z = 7.40, 95% CI: -3.01 (-3.81 to -2.22), P < .00001]; 6 studies show that gamma-glutamyl transpeptidase levels of the experimental group are lower than that of the control group [Z = 2.43, 95% CI: -23.77 (-42.98 to -4.57), P = .02]; 9 studies show that triglyceride levels of the experimental group are lower than that of the control group [Z = 3.06, 95% CI: -0.62 (-1.01 to -0.22), P = .002]; 6 studies show that the homeostasis model assessment of insulin resistance of the experimental group is lower than that of the control group [Z = 3.22, 95% CI: -2.33 (-3.75 to -0.91), P = .001]; 6 studies show that the glycated hemoglobin A1c of the experimental group is lower than that of the control group [Z = 4.50, 95% CI: -1.90 (-2.72 to -1.07), P < .00001]; five studies show that the fasting insulin of the experimental group is lower than that of the control group [Z = 3.42, 95% CI: -2.25 (-3.53 to -0.96), P = .0006]. CONCLUSION Pioglitazone intake is effective in nonalcoholic steatohepatitis management.
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Affiliation(s)
- Yan Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Wenli Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Hongwu Wang
- School of Health science and Engineering, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ye Zhao
- Department of Public Health, International College, Krirk University, Bangkok, Thailand
| | - Huaien Bu
- School of Health Science and Engineering, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga, Japan
- * Correspondence: Hirokazu Takahashi, Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 840-8502, Japan (e-mail: )
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Gangopadhyay A, Ibrahim R, Theberge K, May M, Houseknecht KL. Non-alcoholic fatty liver disease (NAFLD) and mental illness: Mechanisms linking mood, metabolism and medicines. Front Neurosci 2022; 16:1042442. [PMID: 36458039 PMCID: PMC9707801 DOI: 10.3389/fnins.2022.1042442] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/21/2022] [Indexed: 09/26/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world and one of the leading indications for liver transplantation. It is one of the many manifestations of insulin resistance and metabolic syndrome as well as an independent risk factor for cardiovascular disease. There is growing evidence linking the incidence of NAFLD with psychiatric illnesses such as schizophrenia, bipolar disorder and depression mechanistically via genetic, metabolic, inflammatory and environmental factors including smoking and psychiatric medications. Indeed, patients prescribed antipsychotic medications, regardless of diagnosis, have higher incidence of NAFLD than population norms. The mechanistic pharmacology of antipsychotic-associated NAFLD is beginning to emerge. In this review, we aim to discuss the pathophysiology of NAFLD including its risk factors, insulin resistance and systemic inflammation as well as its intersection with psychiatric illnesses.
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Affiliation(s)
| | | | | | | | - Karen L. Houseknecht
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME, United States
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Age-Related NAFLD: The Use of Probiotics as a Supportive Therapeutic Intervention. Cells 2022; 11:cells11182827. [PMID: 36139402 PMCID: PMC9497179 DOI: 10.3390/cells11182827] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/26/2022] [Accepted: 09/08/2022] [Indexed: 11/24/2022] Open
Abstract
Human aging, a natural process characterized by structural and physiological changes, leads to alterations of homeostatic mechanisms, decline of biological functions, and subsequently, the organism becomes vulnerable to external stress or damage. In fact, the elderly population is prone to develop diseases due to deterioration of physiological and biological systems. With aging, the production of reactive oxygen species (ROS) increases, and this causes lipid, protein, and DNA damage, leading to cellular dysfunction and altered cellular processes. Indeed, oxidative stress plays a key role in the pathogenesis of several chronic disorders, including hepatic diseases, such as non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common liver disorder in the Western world, is characterized by intrahepatic lipid accumulation; is highly prevalent in the aging population; and is closely associated with obesity, insulin resistance, hypertension, and dyslipidemia. Among the risk factors involved in the pathogenesis of NAFLD, the dysbiotic gut microbiota plays an essential role, leading to low-grade chronic inflammation, oxidative stress, and production of various toxic metabolites. The intestinal microbiota is a dynamic ecosystem of microbes involved in the maintenance of physiological homeostasis; the alteration of its composition and function, during aging, is implicated in different liver diseases. Therefore, gut microbiota restoration might be a complementary approach for treating NAFLD. The administration of probiotics, which can relieve oxidative stress and elicit several anti-aging properties, could be a strategy to modify the composition and restore a healthy gut microbiota. Indeed, probiotics could represent a valid supplement to prevent and/or help treating some diseases, such as NAFLD, thus improving the already available pharmacological intervention. Moreover, in aging, intervention of prebiotics and fecal microbiota transplantation, as well as probiotics, will provide novel therapeutic approaches. However, the relevant research is limited, and several scientific research works need to be done in the near future to confirm their efficacy.
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Zhang C, Fu Q, Shao K, Liu L, Ma X, Zhang F, Zhang X, Meng L, Yan C, Zhao X. Indole-3-acetic acid improves the hepatic mitochondrial respiration defects by PGC1a up-regulation. Cell Signal 2022; 99:110442. [PMID: 35988807 DOI: 10.1016/j.cellsig.2022.110442] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 08/06/2022] [Accepted: 08/15/2022] [Indexed: 11/26/2022]
Abstract
Recent evidences have linked indole-3-acetic acid (I3A), a gut microbiota-derived metabolite from dietary tryptophan, with the protection against non-alcoholic fatty liver disease (NAFLD). However, the values of I3A on mitochondrial homeostasis in NAFLD have yet to be analyzed. In this study, we verified that I3A alleviated dietary-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis. Importantly, we expanded the understanding of I3A further to enhance mitochondrial oxidative phosphorylation in the liver by RNA-seq. Consistently, I3A restored the deficiency of mitochondrial respiration complex (MRC) capacity in palmitic acid (PA)-induced HepG2 without initiating oxidative stress in vitro. These changes were dependent on peroxisome proliferator-activated receptor γ coactivator 1 (PGC1)-a, a key regulator of mitochondrial biogenesis. Silencing of PGC1a by siRNA and pharmacologic inhibitor SR-18292, blocked the restoration of I3A on mitochondrial oxidative phosphorylation. In addition, pre-treatment of I3A guarded against the deficiency of MRC capacity. In conclusion, our findings uncovered that I3A increased hepatic PGC1a expression, contributing to mitochondrial respiration improvement in NAFLD.
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Affiliation(s)
- Chen Zhang
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - Qingsong Fu
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - Kai Shao
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - Limin Liu
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - Xiaotian Ma
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - Fengyi Zhang
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - Xiaodong Zhang
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - Liying Meng
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - ChuanZhu Yan
- Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China
| | - Xiaoyun Zhao
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266035, China; Qingdao Key Lab of Mitochondrial Medicine, Hefei Road No 758, Qingdao 266035, China.
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Guan Y, Xu Y, Su H, Sun X, Li Y, Wang T. Effect of serum vitamin D on metabolic associated fatty liver disease: a large population-based study. Scand J Gastroenterol 2022; 57:862-871. [PMID: 35170370 DOI: 10.1080/00365521.2022.2039284] [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] [Indexed: 02/04/2023]
Abstract
BACKGROUND Several studies have revealed that serum vitamin D is an important factor for metabolic associated fatty liver disease (MAFLD), but there had been no consistent conclusion. METHODS Of 427,507 subjects who underwent health examination, 83,625 who met the inclusion criteria were included in a cross-sectional analysis. Clinical and laboratory data were collected for analysis. MAFLD was diagnosed by abdominal imaging. RESULTS Multivariate linear regression models discovered a negative association between serum vitamin D and MAFLD (OR: 0.92, 95% CI: 0.90 to 0.94, p = .001), after adjusting for other well-identified risk factors. The same result was found when serum vitamin D was handled as a categorical variable (quartile, Q1-Q4) (Q4 vs. Q1, OR: 0.82, 95% CI: 0.77 to 0.87, p < .001), and a significant linear trend was observed (p for trend <.001). After analysis, a nonlinear relationship was detected between serum vitamin D and MAFLD, with an inflection point of 2.23 (44.6 nmol/L or 17.84 ng/mL). The effect sizes and the confidence intervals on the left and right sides of the inflection point were 1.16 (1.06 to 1.28) and 0.89 (0.86 to 0.91), respectively. All interactions with MAFLD were not significant for age, sex, diabetes, hypertension, smoking and body mass index (p for interaction = .110, .558, .335, .195, .616 and .401, respectively). CONCLUSIONS There was a nonlinear relationship between serum vitamin D and MAFLD. When the serum vitamin D level was ≥44.6 nmol/L (17.84 ng/mL), a negative correlation between serum vitamin D and MAFLD was detected. Below this level, serum vitamin D might promote the progression of MAFLD.
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Affiliation(s)
- Yaqi Guan
- Department of Nursing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yilun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huang Su
- Department of Gastroenterology, Wenzhou Central Hospital, The dingli clinical institute of Wenzhou Medical University, Wenzhou, China
| | - Xuecheng Sun
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanxuan Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Tingting Wang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Ramanathan R, Ali AH, Ibdah JA. Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23137280. [PMID: 35806284 PMCID: PMC9267060 DOI: 10.3390/ijms23137280] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 06/27/2022] [Accepted: 06/29/2022] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global pandemic that affects one-quarter of the world’s population. NAFLD includes a spectrum of progressive liver disease from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis and can be complicated by hepatocellular carcinoma. It is strongly associated with metabolic syndromes, obesity, and type 2 diabetes, and it has been shown that metabolic dysregulation is central to its pathogenesis. Recently, it has been suggested that metabolic- (dysfunction) associated fatty liver disease (MAFLD) is a more appropriate term to describe the disease than NAFLD, which puts increased emphasis on the important role of metabolic dysfunction in its pathogenesis. There is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Impaired mitochondrial fatty acid oxidation and, more recently, a reduction in mitochondrial quality, have been suggested to play a major role in NAFLD development and progression. In this review, we provide an overview of our current understanding of NAFLD and highlight how mitochondrial dysfunction contributes to its pathogenesis in both animal models and human subjects. Further we discuss evidence that the modification of mitochondrial function modulates NAFLD and that targeting mitochondria is a promising new avenue for drug development to treat NAFLD/NASH.
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Affiliation(s)
- Raghu Ramanathan
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, Columbia, MO 65201, USA
| | - Ahmad Hassan Ali
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, Columbia, MO 65201, USA
| | - Jamal A. Ibdah
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA; (R.R.); (A.H.A.)
- Harry S. Truman Memorial Veterans Medical Center, Columbia, MO 65201, USA
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA
- Correspondence: ; Tel.: +573-882-7349; Fax: +573-884-4595
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Mitsala A, Tsalikidis C, Romanidis K, Pitiakoudis M. Non-Alcoholic Fatty Liver Disease and Extrahepatic Cancers: A Wolf in Sheep’s Clothing? Curr Oncol 2022; 29:4478-4510. [PMID: 35877216 PMCID: PMC9325209 DOI: 10.3390/curroncol29070356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/02/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now considered the main driver and leading cause of chronic liver disease globally. The umbrella term NAFLD describes a range of liver conditions closely related to insulin resistance, metabolic syndrome, diabetes mellitus, obesity, and dyslipidemia. At the same time, several malignancies, including hepatocellular carcinoma and colorectal cancer, are considered to be common causes of death among patients with NAFLD. At first, our review herein aims to investigate the role of NAFLD in developing colorectal neoplasms and adenomatous polyps based on the current literature. We will also explore the connection and the missing links between NAFLD and extrahepatic cancers. Interestingly, any relationship between NAFLD and extrahepatic malignancies could be attributable to several shared metabolic risk factors. Overall, obesity, insulin resistance, metabolic syndrome, and related disorders may increase the risk of developing cancer. Therefore, early diagnosis of NAFLD is essential for preventing the progression of the disease and avoiding its severe complications. In addition, cancer screening and early detection in these patients may improve survival and reduce any delays in treatment.
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Pituitary Tumor-Transforming Gene 1/Delta like Non-Canonical Notch Ligand 1 Signaling in Chronic Liver Diseases. Int J Mol Sci 2022; 23:ijms23136897. [PMID: 35805898 PMCID: PMC9267054 DOI: 10.3390/ijms23136897] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/17/2022] [Accepted: 06/18/2022] [Indexed: 02/06/2023] Open
Abstract
The management of chronic liver diseases (CLDs) remains a challenge, and identifying effective treatments is a major unmet medical need. In the current review we focus on the pituitary tumor transforming gene (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) axis as a potential therapeutic target to attenuate the progression of these pathological conditions. PTTG1 is a proto-oncogene involved in proliferation and metabolism. PTTG1 expression has been related to inflammation, angiogenesis, and fibrogenesis in cancer and experimental fibrosis. On the other hand, DLK1 has been identified as one of the most abundantly expressed PTTG1 targets in adipose tissue and has shown to contribute to hepatic fibrosis by promoting the activation of hepatic stellate cells. Here, we extensively analyze the increasing amount of information pointing to the PTTG1/DLK1 signaling pathway as an important player in the regulation of these disturbances. These data prompted us to hypothesize that activation of the PTTG1/DLK1 axis is a key factor upregulating the tissue remodeling mechanisms characteristic of CLDs. Therefore, disruption of this signaling pathway could be useful in the therapeutic management of CLDs.
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Hendawy AS, El-Lakkany NM, Mantawy EM, Hammam OA, Botros SS, El-Demerdash E. Vildagliptin alleviates liver fibrosis in NASH diabetic rats via modulation of insulin resistance, oxidative stress, and inflammatory cascades. Life Sci 2022; 304:120695. [PMID: 35671811 DOI: 10.1016/j.lfs.2022.120695] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023]
Abstract
AIMS This study investigates the therapeutic potential of Vilda in a NASH model with liver fibrosis and elucidates the underlying molecular mechanisms. MAIN METHODS To induce NASH, male Sprague-Dawley rats were fed a high-fat diet for 24 weeks with a single dose of STZ (40 mg/kg, IP). Vilda was orally administered at two doses (10 and 20 mg/kg) for 20 weeks. KEY FINDINGS The induction of NASH was validated by abnormalities in hepatotoxicity indices, lipid profile, oxidative stress markers, and pathologically by marked fat deposition in hepatic tissues together with severe inflammatory cell infiltration. Moreover, NASH-affected rats demonstrated reduced insulin sensitivity manifested as elevated fasting blood glucose levels and disrupted homeostasis model assessment for insulin resistance. Vilda, at both doses, effectively abrogated all these pathological features of NASH. Mechanistically, these hepatoprotective properties of Vilda can be attributed to its antioxidant effects, anti-inflammatory effects (by inhibiting the TNF-α, NF-κB, JNK, and JAK/STAT pathways), and insulin-sensitizing effect (by upregulating the IRS-1/PI3K/Akt pathway). Besides, Vilda successfully counteracted NASH-associated liver fibrosis by downregulating the TGF-β1 pathway. SIGNIFICANCE The hepatoprotective and antifibrotic effects of Vilda were mostly dose-dependent. Collectively, this study offered a promising therapeutic avenue for Vilda as a novel strategy for counteracting the pathological progression of NASH and associated liver fibrosis.
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Affiliation(s)
- Ahmed S Hendawy
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, 30, Giza 12411, Egypt
| | - Naglaa M El-Lakkany
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, 30, Giza 12411, Egypt
| | - Eman M Mantawy
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt
| | - Olfat A Hammam
- Department of Pathology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, 30, Giza 12411, Egypt
| | - Sanaa S Botros
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, 30, Giza 12411, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt.
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Ajah AA, Lembede BW, Nkomozepi P, Erlwanger KH, Nyakudya TT. Neonatal Oral Administration of Chrysin Prevents Long-Term Development of Non-Alcoholic Fatty Liver Disease in a Sexually Dimorphic Manner in Fructose Nurtured Sprague Dawley Rats. Life (Basel) 2022; 12:life12060790. [PMID: 35743821 PMCID: PMC9225280 DOI: 10.3390/life12060790] [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: 03/31/2022] [Revised: 04/30/2022] [Accepted: 05/23/2022] [Indexed: 12/03/2022] Open
Abstract
High-fructose diets are linked with the development of non-alcoholic fatty liver disease (NAFLD), the management of which is a burden to society. Interventions with phytochemicals in the early postnatal period may prevent fructose-induced NAFLD later in adulthood. We investigated the protective potential of chrysin against fructose-induced NAFLD. Four-day-old male and female suckling Sprague Dawley rats (N = 112) were randomly grouped and orally gavaged daily with distilled water (negative Control-Cn + W), chrysin(Chr-100 mg/kg), fructose-solution (Fr-20% w/v), and Chr + Fr between postnatal day (PND) 4 and 21 and then weaned onto normal rat chow and plain drinking water to PND 55. From PND 56 to 130, half of the rats continued on plain water, and the rest had Fr as drinking fluid. Terminally, the liver tissue was collected, and the lipid content was determined and histologically assessed for NAFLD. Dietary Fr induced an increased hepatic lipid content (p = 0.0001 vs. Cn + W) both sexes, and it was only attenuated by neonatal Chr in female rats (p < 0.05). Histologically, there was increased microvesicular steatosis (p = 0.0001 vs. Cn + W) in both sexes, and it was prevented by neonatal Chr (p > 0.05). Fr caused macrovesicular steatosis (p = 0.01 vs. Cn + W) in females only, and chrysin did not prevent it (p > 0.05). Fr induced hepatocellular hypertrophy, and inflammation was observed in females only (p = 0.01 vs. Cn + W), and this was prevented by Chr (p > 0.05). The collagen area fraction was increased by Fr (p = 0.02 (males) and p = 0.04 (females) vs. Cn + W, respectively; however, chrysin did not prevent this (p > 0.05). Neonatal chrysin prevented some of the deleterious effects of the high-fructose diet on the liver, suggesting that chrysin should be further explored as a strategic prophylactic neonatal intervention against high-fructose-diet-induced NAFLD.
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Affiliation(s)
- Austin A. Ajah
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa; (B.W.L.); (K.H.E.)
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Port Harcourt, P.M.B. 5323, Choba, Port Harcourt 500102, Nigeria
- Correspondence:
| | - Busisani W. Lembede
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa; (B.W.L.); (K.H.E.)
| | - Pilani Nkomozepi
- Department of Human Anatomy and Physiology, Faculty of Health Sciences, University of Johannesburg, Corner Beit and Siemert Street, Doornfontein, Johannesburg 2094, South Africa; (P.N.); (T.T.N.)
| | - Kennedy H. Erlwanger
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa; (B.W.L.); (K.H.E.)
| | - Trevor T. Nyakudya
- Department of Human Anatomy and Physiology, Faculty of Health Sciences, University of Johannesburg, Corner Beit and Siemert Street, Doornfontein, Johannesburg 2094, South Africa; (P.N.); (T.T.N.)
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina, Pretoria 0031, South Africa
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Espinoza-Derout J, Shao XM, Lao CJ, Hasan KM, Rivera JC, Jordan MC, Echeverria V, Roos KP, Sinha-Hikim AP, Friedman TC. Electronic Cigarette Use and the Risk of Cardiovascular Diseases. Front Cardiovasc Med 2022; 9:879726. [PMID: 35463745 PMCID: PMC9021536 DOI: 10.3389/fcvm.2022.879726] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Abstract
Electronic cigarettes or e-cigarettes are the most frequently used tobacco product among adolescents. Despite the widespread use of e-cigarettes and the known detrimental cardiac consequences of nicotine, the effects of e-cigarettes on the cardiovascular system are not well-known. Several in vitro and in vivo studies delineating the mechanisms of the impact of e-cigarettes on the cardiovascular system have been published. These include mechanisms associated with nicotine or other components of the aerosol or thermal degradation products of e-cigarettes. The increased hyperlipidemia, sympathetic dominance, endothelial dysfunction, DNA damage, and macrophage activation are prominent effects of e-cigarettes. Additionally, oxidative stress and inflammation are unifying mechanisms at many levels of the cardiovascular impairment induced by e-cigarette exposure. This review outlines the contribution of e-cigarettes in the development of cardiovascular diseases and their molecular underpinnings.
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Affiliation(s)
- Jorge Espinoza-Derout
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Xuesi M. Shao
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Candice J. Lao
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
| | - Kamrul M. Hasan
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Juan Carlos Rivera
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
| | - Maria C. Jordan
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Valentina Echeverria
- Research and Development Service, Bay Pines VA Healthcare System, Bay Pines, FL, United States
- Laboratorio de Neurobiología, Facultad de Ciencias de la Salud, Universidad San Sebastián, Concepción, Chile
| | - Kenneth P. Roos
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Amiya P. Sinha-Hikim
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Theodore C. Friedman
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Friends Research Institute, Cerritos, CA, United States
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Role of a Novel Silver Fir (Abies alba) Extract, Abigenol®/AlbiPhenol®, in Modulating Cardiovascular Disorders: Key Factors. Antioxidants (Basel) 2022; 11:antiox11040618. [PMID: 35453303 PMCID: PMC9024870 DOI: 10.3390/antiox11040618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 12/05/2022] Open
Abstract
Cardiovascular diseases (CVDs) represent the leading cause of death worldwide, being responsible for about one third of deaths. Among CVDs, coronary artery diseases (CADs) are characterized by vascular endothelium dysfunction due to oxidative and inflammatory damages, the oxidation of circulating low-density lipoproteins (LDL) and high-density lipoproteins (HDL), and the production of ROS in the steatotic liver with the consequent increase of lipids and cholesterol. Together with CADs, heart failure (HF) represents another high-mortality rate CVD. A major risk factor for HF is hypertension that is accompanied by oxidative stress. Phytoextracts, rich in antioxidant and anti-inflammatory compounds, may have therapeutic value as they can interfere with several CVDs risk factors. In this work, a novel silver fir (Abies alba) bark extract, Abigenol®/AlbiPhenol®, was studied. First, Abigenol®/AlbiPhenol® cytotoxicity, bioaccessibility and bioavailability were evaluated by using an in vitro digestion model. Abigenol®/AlbiPhenol® was shown to be non-cytotoxic and showed good bioaccessibility. Then, by using in vitro hepatic, cardiac and vascular models, its antioxidant and anti-steatotic properties were assessed. Abigenol®/AlbiPhenol® showed an effective antioxidant action, and it was able to inhibit LDL and HDL oxidation, the main actors in atherosclerotic plaque formation. In steatotic conditions, Abigenol®/AlbiPhenol® induces decreased lipid and cholesterol accumulation in hepatocytes. In addition, in a cardiac model, the formulation reduced the activity of the hypertension-related angiotensin-converting enzyme (ACE). Altogether, these findings reveal a potential application of Abigenol®/AlbiPhenol® in the prevention and treatment of CVDs.
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Diagnostic Modalities of Non-Alcoholic Fatty Liver Disease: From Biochemical Biomarkers to Multi-Omics Non-Invasive Approaches. Diagnostics (Basel) 2022; 12:diagnostics12020407. [PMID: 35204498 PMCID: PMC8871470 DOI: 10.3390/diagnostics12020407] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 02/05/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common cause of chronic liver disease worldwide, and its prevalence is increasing globally. NAFLD is a multifaceted disorder, and its spectrum includes steatosis to steatohepatitis, which may evolve to advanced fibrosis and cirrhosis. In addition, the presence of NAFLD is independently associated with a higher cardiometabolic risk and increased mortality rates. Considering that the vast majority of individuals with NAFLD are mainly asymptomatic, early diagnosis of non-alcoholic steatohepatitis (NASH) and accurate staging of fibrosis risk is crucial for better stratification, monitoring and targeted management of patients at risk. To date, liver biopsy remains the gold standard procedure for the diagnosis of NASH and staging of NAFLD. However, due to its invasive nature, research on non-invasive tests is rapidly increasing with significant advances having been achieved during the last decades in the diagnostic field. New promising non-invasive biomarkers and techniques have been developed, evaluated and assessed, including biochemical markers, imaging modalities and the most recent multi-omics approaches. Our article provides a comprehensive review of the currently available and emerging non-invasive diagnostic tools used in assessing NAFLD, also highlighting the importance of accurate and validated diagnostic tools.
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Han X, Zhao W, Zhou Q, Chen H, Yuan J, Zhang XF, Zhang Z. Procyanidins from Hawthorn ( Crataegus Pinnatifida) Alleviates Lipid Metabolism Disorder via Inhibiting Insulin Resistance and Oxidative Stress, Normalizing Gut Microbiota Structure and Intestinal Barrier, Further Suppressing Hepatic Inflammation and Lipid Accumulation. Food Funct 2022; 13:7901-7917. [DOI: 10.1039/d2fo00836j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Recently, lipid metabolism disorder (LMD) has been regarded as a risky factor leading to multiple diseases and affecting human health. Procyanidins have been reported to be the potential therapy for...
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