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Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
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Gu S, Qiao Y, Liu S, Yang S, Cong S, Wang S, Yu D, Wang W, Chai X. Frontiers and hotspots of adipose tissue and NAFLD: a bibliometric analysis from 2002 to 2022. Front Physiol 2023; 14:1278952. [PMID: 38187139 PMCID: PMC10768199 DOI: 10.3389/fphys.2023.1278952] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 12/04/2023] [Indexed: 01/09/2024] Open
Abstract
Background: The annual incidence of non-alcoholic fatty liver disease (NAFLD) continues to rise steadily. In recent years, adipose tissue (AT) has gained recognition as a pivotal contributor to the pathogenesis of NAFLD. Employing bibliometric analysis, we examined literature concerning AT and NAFLD. Methods: Relevant literature on AT in NAFLD from 1980 to 2022 was extracted from the Web of Science Core Collection. These records were visualized using CiteSpace and VOSviewer regarding publications, countries/regions, institutions, authors, journals, references, and keywords. Results: Since 2002, a total of 3,330 papers have been included, exhibiting an annual surge in publications. Notably, the quality of publications is superior in the USA and Europe. Kenneth Cusi stands out as the author with the highest number of publications and H-index. Hepatology is the journal boasting the highest citation and H-index. The University of California System holds the highest centrality among institutions. References specifically delve into physiological processes associated with AT in NAFLD. Currently, lipid metabolism and inflammation constitute the principal research mechanisms in the AT-based regulation of NAFLD, with pertinent keywords including microRNA, T cell, hypoxia, sarcopenia, hepatokine, gut microbiota, and autophagy. The Mediterranean diet is among the most widely recommended dietary approaches for potential NAFLD treatment. Conclusion: This paper represents the inaugural bibliometric study on the effects of AT on NAFLD, offering valuable insights and directions for future research.
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Affiliation(s)
- Shuxiao Gu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yanfang Qiao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Susu Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shuangjie Yang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Shibo Cong
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Sili Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Deshuai Yu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Wei Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xinlou Chai
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Pan J, Ding Y, Sun Y, Li Q, Wei T, Gu Y, Zhou Y, Pang N, Pei L, Ma S, Gao M, Xiao Y, Hu D, Wu F, Yang L. Associations between Adipokines and Metabolic Dysfunction-Associated Fatty Liver Disease Using Three Different Diagnostic Criteria. J Clin Med 2023; 12:jcm12062126. [PMID: 36983127 PMCID: PMC10051925 DOI: 10.3390/jcm12062126] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/11/2023] Open
Abstract
Background: A panel of experts proposed a new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) in 2020. To date, the associations between adipokines, such as adiponectin, adipsin, and visfatin and MAFLD remain unclear. Therefore, we aimed to evaluate the associations between each of these three adipokines and MAFLD using different diagnostic criteria. Methods: In total, 221 participants were included in our study based on medical examination. Detailed questionnaire information, physical examination, abdominal ultrasound, and blood-biochemical-test indexes were collected. The levels of adipokines were tested by using an enzyme immunoassay. Logistic regression models were used to assess the associations of the adipokines with MAFLD. Results: In total, 122 of the participants were diagnosed with MAFLD. Higher levels of adipsin and lower levels of adiponectin were found in the MAFLD group than in the non-MAFLD group (all p < 0.05). According to the logistic regression analysis, the ORs were 0.11 (95% CI: 0.05–0.23) for adiponectin, 4.46 (95% CI: 2.19–9.12) for adipsin, and 0.51 (95% CI: 0.27–0.99) for visfatin when comparing the highest tertile with the lowest tertile (all p-trend < 0.05). The inverse association between adiponectin and MAFLD was strongest when T2DM was used as the diagnostic criterion alone, and the positive association between adipsin and MAFLD was strongest when BMI was used as the diagnostic criterion alone. There was no significant association between visfatin and MAFLD, regardless of whether each of BMI, T2DM, or metabolic dysregulation (MD) was used as the diagnostic criterion for MAFLD alone. Conclusion: Adipsin levels were positively associated with MAFLD and adiponectin levels were inversely associated with MAFLD. The strength of these associations varied according to the different diagnostic criteria for MAFLD.
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Affiliation(s)
- Jie Pan
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yijie Ding
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yan Sun
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Qiuyan Li
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Tianyi Wei
- Department of Obstetrics, The First Women and Children’s Hospital of Huizhou, Huizhou 516000, China
| | - Yingying Gu
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yujia Zhou
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Nengzhi Pang
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Lei Pei
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Sixi Ma
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Mengqi Gao
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Ying Xiao
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - De Hu
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Feilong Wu
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Lili Yang
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
- Correspondence: ; Tel.: +86-20-87330625
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Shen W, Middleton MS, Cunha GM, Delgado TI, Wolfson T, Gamst A, Fowler KJ, Alazraki A, Trout AT, Ohliger MA, Shah SN, Bashir MR, Kleiner DE, Loomba R, Neuschwander-Tetri BA, Sanyal AJ, Zhou J, Sirlin CB, Lavine JE. Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis. J Hepatol 2023; 78:238-246. [PMID: 36368598 PMCID: PMC9852022 DOI: 10.1016/j.jhep.2022.10.027] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is prevalent in adults with obesity and can progress to cirrhosis. In a secondary analysis of prospectively acquired data from the multicenter, randomized, placebo-controlled FLINT trial, we investigated the relationship between reduction in adipose tissue compartment volumes and hepatic histologic improvement. METHODS Adult participants in the FLINT trial with paired liver biopsies and abdominal MRI exams at baseline and end-of-treatment (72 weeks) were included (n = 76). Adipose tissue compartment volumes were obtained using MRI. RESULTS Treatment and placebo groups did not differ in baseline adipose tissue volumes, or in change in adipose tissue volumes longitudinally (p = 0.107 to 0.745). Deep subcutaneous adipose tissue (dSAT) and visceral adipose tissue volume reductions were associated with histologic improvement in NASH (i.e., NAS [non-alcoholic fatty liver disease activity score] reductions of ≥2 points, at least 1 point from lobular inflammation and hepatocellular ballooning, and no worsening of fibrosis) (p = 0.031, and 0.030, respectively). In a stepwise logistic regression procedure, which included demographics, treatment group, baseline histology, baseline and changes in adipose tissue volumes, MRI hepatic proton density fat fraction (PDFF), and serum aminotransferases as potential predictors, reductions in dSAT and PDFF were associated with histologic improvement in NASH (regression coefficient = -2.001 and -0.083, p = 0.044 and 0.033, respectively). CONCLUSIONS In adults with NASH in the FLINT trial, those with greater longitudinal reductions in dSAT and potentially visceral adipose tissue volumes showed greater hepatic histologic improvements, independent of reductions in hepatic PDFF. CLINICAL TRIAL NUMBER NCT01265498. IMPACT AND IMPLICATIONS Although central obesity has been identified as a risk factor for obesity-related disorders including insulin resistance and cardiovascular disease, the role of central obesity in non-alcoholic steatohepatitis (NASH) warrants further clarification. Our results highlight that a reduction in central obesity, specifically deep subcutaneous adipose tissue and visceral adipose tissue, may be related to histologic improvement in NASH. The findings from this analysis should increase awareness of the importance of lifestyle intervention in NASH for clinical researchers and clinicians. Future studies and clinical practice may design interventions that assess the reduction of deep subcutaneous adipose tissue and visceral adipose tissue as outcome measures, rather than simply weight reduction.
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Affiliation(s)
- Wei Shen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA;; Institute of Human Nutrition, College of Physicians & Surgeons, Columbia University Irving Medical Center; NY, USA;; Columbia Magnetic Resonance Research Center (CMRRC), Columbia University, USA.
| | - Michael S Middleton
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | | | - Timoteo I Delgado
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | - Tanya Wolfson
- Computational and Applied Statistics Laboratory (CASL), San Diego Supercomputer Center at UCSD, San Diego, CA, USA
| | - Anthony Gamst
- Computational and Applied Statistics Laboratory (CASL), San Diego Supercomputer Center at UCSD, San Diego, CA, USA;; Department of Mathematics, UCSD, San Diego, CA, USA
| | - Kathryn J Fowler
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | - Adina Alazraki
- Emory University School of Medicine, Department of Radiology and Imaging Sciences and Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Andrew T Trout
- Department of Radiology, Cincinnati Children's Hospital Medical Center and Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michael A Ohliger
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - Shetal N Shah
- Section of Abdominal Imaging and Nuclear Medicine Department, Imaging Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mustafa R Bashir
- Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA;; Center for Advanced Magnetic Resonance Development, (CAMRD), Department of Radiology, Duke University Medical Center, Durham, NC, USA;; Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California-San Diego, La Jolla, CA, USA
| | | | | | - Jane Zhou
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, UCSD School of Medicine, San Diego, CA, USA
| | - Joel E Lavine
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA;; Institute of Human Nutrition, College of Physicians & Surgeons, Columbia University Irving Medical Center; NY, USA
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Nong YB, Huang HN, Huang JJ, Du YQ, Song WX, Mao DW, Zhong YX, Zhu RH, Xiao XY, Zhong RX. Rare leptin in non-alcoholic fatty liver cirrhosis: A case report. World J Clin Cases 2022; 10:10293-10300. [PMID: 36246792 PMCID: PMC9561580 DOI: 10.12998/wjcc.v10.i28.10293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/27/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD)-related cirrhosis is mainly caused by NAFLD by causing inflammation which leads to fibrosis. The role of leptin in NAFLD-related cirrhosis has been rarely reported.
CASE SUMMARY This study presents the case of a 65-year-old male patient who was referred to The First Affiliated Hospital of Guangxi University of Chinese Medicine, Guangxi, China, for diagnosis and treatment for liver cirrhosis. Initially, the cause of liver cirrhosis was unknown. After radiology, laboratory examination, pathological results and analysis of the patient’s signs and symptoms, the case was finally diagnosed with final NAFLD-related cirrhosis. Although this study reports a single case, the findings might expand the understanding of leptin’s role in NAFLD-related cirrhosis and might provide a basis for the clinical diagnostic criteria, pathological features and treatment of NAFLD-related cirrhosis.
CONCLUSION Although the occurrence of marasmus NAFLD-related cirrhosis is rare, it needs to be distinguished from other liver diseases, including viral hepatitis, drug-induced liver disease, Wilson's disease and autoimmune liver disease. Aggressive treatment is needed to prevent the progression of NAFLD-related cirrhosis.
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Affiliation(s)
- Yao-Bin Nong
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Hong-Na Huang
- Department of Internal Medicine of Traditional Chinese Medicine,The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Jing-Jing Huang
- Department of Spleen and Stomach Liver Diseases, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Yuan-Qin Du
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Wen-Xuan Song
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - De-Wen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region, China
| | - Yue-Xue Zhong
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Rong-Huo Zhu
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Xi-Yu Xiao
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Rui-Xi Zhong
- The First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530022, Guangxi Zhuang Autonomous Region, China
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Effects of aerobic exercise and resveratrol on adipocytokines in rats with nonalcoholic fatty liver disease. Sci Sports 2022. [DOI: 10.1016/j.scispo.2021.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Coffee consumption has no effect on circulating markers of liver function but increases adiponectin concentrations: a systematic review and meta-analysis of randomized controlled trials. Nutr Res 2022; 106:24-34. [PMID: 36126527 DOI: 10.1016/j.nutres.2022.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 07/27/2022] [Accepted: 07/30/2022] [Indexed: 11/18/2022]
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Ebrahimi R, Shanaki M, Mohassel Azadi S, Bahiraee A, Radmard AR, Poustchi H, Emamgholipour S. Low level of adiponectin predicts the development of Nonalcoholic fatty liver disease: is it irrespective to visceral adiposity index, visceral adipose tissue thickness and other obesity indices? Arch Physiol Biochem 2022; 128:24-31. [PMID: 31482741 DOI: 10.1080/13813455.2019.1661496] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We aimed to study the correlation of adiponectin level with insulin resistance (IR), carotid intima-media thickness (cIMT), and various obesity indices especially visceral adipose tissue (VAT) thickness, and visceral adiposity index (VAI), in patients with NAFLD (n = 41), T2D (n = 22), NAFLD + T2D (n = 41), and healthy subjects (n = 20). Results showed the median level of adiponectin in patients with NAFLD (2.97 μg/mL) and ones with NAFLD + T2D (3.21 μg/mL) is significantly lower rather than in controls (4.39 μg/mL). Moreover, VAI is the only predictor for adiponectin concentration in the combination of patient groups and also in all participants independent of IR and other obesity indices. Adiponectin level had also a positive correlation with cIMT and IR in NAFLD patients. Interestingly, lower level of adiponectin was associated with the presence of T2D, NAFLD, and NAFLD + T2D independent of IR and obesity indices. Collectively, it seems that VAI reflecting visceral adipose tissue function is a possible predictor of adiponectin level.
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Affiliation(s)
- Reyhane Ebrahimi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrnoosh Shanaki
- Department of Medical Laboratory Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Mohassel Azadi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Bahiraee
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Amir Reza Radmard
- Department of Radiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Solaleh Emamgholipour
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Iacob SA, Iacob DG. Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients - a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown. Front Endocrinol (Lausanne) 2022; 13:814209. [PMID: 35355551 PMCID: PMC8959898 DOI: 10.3389/fendo.2022.814209] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/10/2022] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and is one of the most prevalent comorbidities in HIV and HBV infected patients. HIV plays an early and direct role in the development of metabolic syndrome by disrupting the mechanism of adipogenesis and synthesis of adipokines. Adipokines, molecules that regulate the lipid metabolism, also contribute to the progression of NAFLD either directly or via hepatic organokines (hepatokines). Most hepatokines play a direct role in lipid homeostasis and liver inflammation but their role in the evolution of NAFLD is not well defined. The role of HBV in the pathogenesis of NAFLD is controversial. HBV has been previously associated with a decreased level of triglycerides and with a protective role against the development of steatosis and metabolic syndrome. At the same time HBV displays a high fibrogenetic and oncogenetic potential. In the HIV/HBV co-infection, the metabolic changes are initiated by mitochondrial dysfunction as well as by the fatty overload of the liver, two interconnected mechanisms. The evolution of NAFLD is further perpetuated by the inflammatory response to these viral agents and by the variable toxicity of the antiretroviral therapy. The current article discusses the pathogenic changes and the contribution of the hepatokine/adipokine axis in the development of NAFLD as well as the implications of HIV and HBV infection in the breakdown of the hepatokine/adipokine axis and NAFLD progression.
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Affiliation(s)
- Simona Alexandra Iacob
- Department of Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Infectious Diseases, National Institute of Infectious Diseases “Prof. Dr. Matei Bals”, Bucharest, Romania
| | - Diana Gabriela Iacob
- Department of Infectious Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- Department of Infectious Diseases, Emergency University Hospital, Bucharest, Romania
- *Correspondence: Diana Gabriela Iacob,
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Wu X, Wang Y, Jia Y, Liu J, Wang G. Risk Factors for Nonalcoholic Fatty Liver Disease with Different Insulin Resistance in a Nonobese Chinese Population. J Diabetes Res 2022; 2022:9060405. [PMID: 36568964 PMCID: PMC9771661 DOI: 10.1155/2022/9060405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
PURPOSES The aim of this study is to identify the risk factors of nonobese nonalcoholic fatty liver disease (NAFLD) individuals under different insulin resistance status. METHODS This cross-sectional study was conducted at the Medical Center of Beijing Chaoyang Hospital affiliated with Capital Medical University. NAFLD was diagnosed based upon ultrasonographic findings consistent with fatty liver disease. RESULTS A total of 1257 nonobese adults (625 non-NAFLD and 632 nonobese NAFLD) with body mass index (BMI) 18.5-24.9 kg/m2 were enrolled in the study. And all patients were divided into homeostasis model assessment of insulin resistance (HOMA - IR) > 1 group and HOMA - IR ≤ 1 group. When all the variables were adjusted in both the HOMA - IR > 1 group and HOMA - IR ≤ 1 group, older age (>50 years), higher BMI (23.0-24.9 kg/m2), higher AST (>18 U/L), higher TG (>0.9 mmol/L), higher GLU (>5.25 mmol/L), and higher HbA1C (>5.5%) were associated with higher risks of nonobese NAFLD. In patients with HOMA - IR > 1, lower homeostatic model assessment of β-cell function (HOMA-β) (<47.1%) (OR, 7.460, 95% CI, 3.051-18.238, P < 0.001) was associated with higher risks of nonobese NAFLD. CONCLUSION s. Metabolic profiles (i.e., higher BMI, hyperglycemia, hypertriglyceridemia, and higher glycosylated hemoglobin) are risk factors of nonobese NAFLD, regardless of insulin resistance status. Decreased function of pancreatic β-cells may be the risk factor of nonobese NAFLD with insulin resistance, who should pay attention to further development of pancreatic β-cell dysfunction.
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Affiliation(s)
- Xiaojuan Wu
- Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing 100020, China
| | - Ying Wang
- Department of Medical Center, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing 100020, China
| | - Yumei Jia
- Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing 100020, China
| | - Jia Liu
- Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing 100020, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing 100020, China
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Mavilia MG, Wu GY. Liver and serum adiponectin levels in non-alcoholic fatty liver disease. J Dig Dis 2021; 22:214-221. [PMID: 33675573 DOI: 10.1111/1751-2980.12980] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/13/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Adiponectin is an adipokine that has anti-steatotic, anti-inflammatory and anti-fibrotic effects. The impact of these different activities impact on the development and progression of non-alcoholic fatty liver disease (NAFLD) is not well understood. The aim of this study was to evaluate both liver and serum adiponectin levels in patients with and without NAFLD and determine any clinical correlations. METHODS Liver tissue and serum samples were collected from patients undergoing liver biopsy between April 2014 and July 2020, and categorized based on histopathological diagnosis into hepatic steatosis (HS), non-alcoholic steatohepatitis (NASH), and hepatitis control (HC). A Luminex xMAP assay was performed on both liver and serum samples to measure adiponectin levels. Statistical analysis compared liver adiponectin (LA) and serum adiponectin (SA) levels between groups. RESULTS A total of 48 participants were included in the analysis. The mean LA level was lowest in the HS group, followed by the NASH group and the HC group (P = 0.036). The mean SA level was 3.61 μg/mL for the NAFLD group and was significantly lower than that in the HC (7.51 μg/mL; P = 0.001). CONCLUSION Adiponectin levels are lower in NAFLD compared to HC in both serum and liver tissue. LA levels in patients with HS were significantly lower than in both the NASH and HC groups, suggesting that adiponectin is related to inflammation in the liver and probably reflects its role in the pathogenesis of NAFLD.
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Affiliation(s)
- Marianna G Mavilia
- Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - George Y Wu
- Department of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, Connecticut, USA
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12
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Genistein Modulated Lipid Metabolism, Hepatic PPARγ, and Adiponectin Expression in Bilateral Ovariectomized Rats with Nonalcoholic Steatohepatitis (NASH). Antioxidants (Basel) 2020; 10:antiox10010024. [PMID: 33383845 PMCID: PMC7824652 DOI: 10.3390/antiox10010024] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/17/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
The aim of this study was to evaluate the protective effects of genistein on lipid accumulation and apoptosis in estrogen deficient rats with NASH. Female Sprague-Dawley rats (n = 48) were divided into ovariectomized (OVX) and non-OVX groups. Each group was then sub-divided into 3 subgroups; control, NASH (rats fed with a high-fat, high-fructose (HFHF) diet), and NASH+Gen (rats fed with HFHF diet plus daily genistein at 16 mg/kg BW). Results showed that HFHF diet induced liver fat accumulation in both non-OVX and OVX rats, which was evidenced by hepatic steatosis on liver pathology and increased hepatic free fatty acid (FFA) and triglyceride levels. Hepatic fat accumulation was significantly more severe in NASH rats with OVX than non-OVX. Hepatocyte apoptosis was more severe in NASH groups compared with that in control groups. Genistein administration significantly improved histopathology of NASH in both non-OVX and OVX rats and attenuated hepatic lipid accumulation, oxidative stress, and hepatocyte apoptosis. Genistein also down-regulated PPARγ and up-regulated adiponectin expression. In summary, NASH could be worsened by estrogen deficiency, indicating the protective action of estrogen on NASH. Genistein administration alleviated hepatic steatosis and apoptosis through the down-regulation of PPARγ and up-regulation of adiponectin expression.
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13
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Kizivat T, Maric I, Mudri D, Curcic IB, Primorac D, Smolic M. Hypothyroidism and Nonalcoholic Fatty Liver Disease: Pathophysiological Associations and Therapeutic Implications. J Clin Transl Hepatol 2020; 8:347-353. [PMID: 33083258 PMCID: PMC7562794 DOI: 10.14218/jcth.2020.00027] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/05/2020] [Accepted: 06/28/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a complex clinical entity which can be secondary to many other diseases including hypothyroidism, characterized by lowering of thyroid hormones and increased thyroid stimulating hormone (TSH). A lot of emerging data published recently advocates the hypothesis that hypothyroid induced NAFLD could be a separate clinical entity, even suggesting possible treatment options for NAFLD involving substitution therapy for hypothyroidism along with lifestyle modifications. In addition, a whole new field of research is focused on thyromimetics in NAFLD/NASH treatment, currently in phase 3 clinical trials. In this critical review we summarized epidemiological and pathophysiological evidence linking these two clinical entities and described specific treatment options with the accent on promising new agents in NAFLD treatment, specifically thyroid hormone receptor (THR) agonist and its metabolites.
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Affiliation(s)
- Tomislav Kizivat
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University Hospital Osijek, Osijek, Croatia
| | - Ivana Maric
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University Hospital Osijek, Osijek, Croatia
| | - Dunja Mudri
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University Hospital Osijek, Osijek, Croatia
| | - Ines Bilic Curcic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University Hospital Osijek, Osijek, Croatia
| | - Dragan Primorac
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- St Catherine Specialty Hospital, Zagreb & Zabok, Croatia
- University of Split School of Medicine, Split, Croatia
- Eberly College of Science, State College, Penn State University, PA, USA
- The Henry C Lee College of Criminal Justice & Forensic Sciences, University of New Haven, West Haven, CT, USA
- University of Rijeka School of Medicine, Rijeka, Croatia
- University of Osijek Faculty of Dental Medicine & Health, Osijek, Croatia
| | - Martina Smolic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek Faculty of Dental Medicine & Health, Osijek, Croatia
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14
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Kojima M, Takahashi H, Kuwashiro T, Tanaka K, Mori H, Ozaki I, Kitajima Y, Matsuda Y, Ashida K, Eguchi Y, Anzai K. Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis. Int J Mol Sci 2020; 21:ijms21165722. [PMID: 32785012 PMCID: PMC7460814 DOI: 10.3390/ijms21165722] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive β-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.
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Affiliation(s)
- Motoyasu Kojima
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Takuya Kuwashiro
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Hitoe Mori
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Iwata Ozaki
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
| | - Yoichiro Kitajima
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Department of Radiology, Eguchi Hospital, Ogi 845-0032, Japan
| | - Yayoi Matsuda
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kenji Ashida
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Yuichiro Eguchi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Liver Center, Saga University Hospital, Faculty of Medicine, Saga University, Saga 849-8501, Japan
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (M.K.); (H.T.); (T.K.); (K.T.); (H.M.); (I.O.); (Y.K.); (Y.M.); (K.A.); (Y.E.)
- Correspondence: ; Tel./Fax: +81-952-34-2362
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15
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Araki N, Takahashi H, Takamori A, Kitajima Y, Hyogo H, Sumida Y, Tanaka S, Anzai K, Aishima S, Chayama K, Fujimoto K, Eguchi Y. Decrease in fasting insulin secretory function correlates with significant liver fibrosis in Japanese non-alcoholic fatty liver disease patients. JGH OPEN 2020; 4:929-936. [PMID: 33102766 PMCID: PMC7578285 DOI: 10.1002/jgh3.12367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 05/14/2020] [Indexed: 12/28/2022]
Abstract
Background and Aim Non‐alcoholic fatty liver disease (NAFLD) is typically associated with metabolic syndrome and diabetes, and insulin resistance is involved in its pathogenesis. However, the relationship between insulin secretion and NAFLD is unclear. We aimed to characterize the relationship between fasting insulin secretory function (ISF), evaluated using the homeostatic model assessment‐beta cell function (HOMA‐β) and the severity of fibrosis during NAFLD. Methods A‐β was calculated in 188 patients with biopsy‐confirmed NAFLD, and the correlations between Log HOMA‐β and clinical parameters, including hepatic fibrosis, were calculated. Results Log HOMA‐β was significantly lower in NAFLD patients with significant fibrosis (stages 2–4) than in those in the early stages (stages 0–1) (median [interquartile range]) (2.1 [1.9–2.4] vs 2.0 [1.8–2.2], P = 0.04). The prevalence of significant fibrosis decreased with increasing Log HOMA‐β: it was 59.2% in participants with low ISF (Log HOMA‐β < 1.85), 43.6% in those with intermediate ISF (1.85 ≤ Log HOMA‐β < 2.25), and 68.0% in those with high ISF (Log HOMA‐β ≥ 2.25). Patients with lower Log HOMA‐β had lower current body mass index (BMI), BMI at 20 years of age, and peak lifetime BMI than patients with intermediate or high Log HOMA‐β. Conclusions Fasting ISF decreased alongside the development of liver fibrosis in NAFLD, suggesting that an impaired β cell function has a characteristic finding of significant liver fibrosis in relatively nonobese Japanese patients.
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Affiliation(s)
- Norimasa Araki
- Department of Internal Medicine, Faculty of Medicine Saga University Saga Japan
| | - Hirokazu Takahashi
- Department of Internal Medicine, Faculty of Medicine Saga University Saga Japan
| | - Ayako Takamori
- Clinical Research Center Saga University Hospital Saga Japan
| | - Yoichiro Kitajima
- Department of Internal Medicine, Faculty of Medicine Saga University Saga Japan.,Liver Center Saga University Hospital Saga Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology JA Hiroshima General Hospital Hatsukaichi Japan
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine Aichi Medical University Aichi Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Disease Nara City Hospital Nara Japan
| | - Keizo Anzai
- Department of Internal Medicine, Faculty of Medicine Saga University Saga Japan
| | - Shinichi Aishima
- Department of Pathology & Microbiology, Faculty of Medicine Saga University Saga Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism Graduate School of Biomedical and Health Sciences, Hiroshima University Hiroshima Japan
| | - Kazuma Fujimoto
- Faculty of Medicine International University of Health and Welfare Fukuoka Japan
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16
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Zhang S, Wong YT, Tang KY, Kwan HY, Su T. Chinese Medicinal Herbs Targeting the Gut-Liver Axis and Adipose Tissue-Liver Axis for Non-Alcoholic Fatty Liver Disease Treatments: The Ancient Wisdom and Modern Science. Front Endocrinol (Lausanne) 2020; 11:572729. [PMID: 33101207 PMCID: PMC7556113 DOI: 10.3389/fendo.2020.572729] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/14/2020] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. The pathogenesis of NAFLD is complex. Frontline western medicines only ameliorate the symptoms of NAFLD. On the contrary, the uniqueness of Chinese medicine in its interpretation of NAFLD and the holistic therapeutic approach lead to a promising therapeutic efficacy. Recent studies reveal that the gut-liver axis and adipose tissue-liver axis play important roles in the development of NAFLD. Interestingly, with advanced technology, many herbal formulae are found to target the gut-liver axis and adipose tissue-liver axis and resolve the inflammation in NAFLD. This is the first review summarizes the current findings on the Chinese herbal formulae that target the two axes in NAFLD treatment. This review not only demonstrates how the ancient wisdom of Chinese medicine is being interpreted by modern pharmacological studies, but also provides valuable information for the further development of the herbal-based treatment for NAFLD.
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Affiliation(s)
- Shuwei Zhang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yui-Tung Wong
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Ka-Yu Tang
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Hiu-Yee Kwan
- Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
- *Correspondence: Hiu-Yee Kwan, ; Tao Su,
| | - Tao Su
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Hiu-Yee Kwan, ; Tao Su,
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17
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Marjot T, Moolla A, Cobbold JF, Hodson L, Tomlinson JW. Nonalcoholic Fatty Liver Disease in Adults: Current Concepts in Etiology, Outcomes, and Management. Endocr Rev 2020; 41:5601173. [PMID: 31629366 DOI: 10.1210/endrev/bnz009] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 10/14/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disease, extending from simple steatosis to inflammation and fibrosis with a significant risk for the development of cirrhosis. It is highly prevalent and is associated with significant adverse outcomes both through liver-specific morbidity and mortality but, perhaps more important, through adverse cardiovascular and metabolic outcomes. It is closely associated with type 2 diabetes and obesity, and both of these conditions drive progressive disease toward the more advanced stages. The mechanisms that govern hepatic lipid accumulation and the predisposition to inflammation and fibrosis are still not fully understood but reflect a complex interplay between metabolic target tissues including adipose and skeletal muscle, and immune and inflammatory cells. The ability to make an accurate assessment of disease stage (that relates to clinical outcome) can also be challenging. While liver biopsy is still regarded as the gold-standard investigative tool, there is an extensive literature on the search for novel noninvasive biomarkers and imaging modalities that aim to accurately reflect the stage of underlying disease. Finally, although no therapies are currently licensed for the treatment of NAFLD, there are interventions that appear to have proven efficacy in randomized controlled trials as well as an extensive emerging therapeutic landscape of new agents that target many of the fundamental pathophysiological processes that drive NAFLD. It is highly likely that over the next few years, new treatments with a specific license for the treatment of NAFLD will become available.
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Affiliation(s)
- Thomas Marjot
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, Oxford, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Ahmad Moolla
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jeremy F Cobbold
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK
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18
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Marchisello S, Di Pino A, Scicali R, Urbano F, Piro S, Purrello F, Rabuazzo AM. Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview. Int J Mol Sci 2019; 20:ijms20081948. [PMID: 31010049 PMCID: PMC6514656 DOI: 10.3390/ijms20081948] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 04/18/2019] [Accepted: 04/20/2019] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed.
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Affiliation(s)
- Simona Marchisello
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Antonino Di Pino
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Roberto Scicali
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Francesca Urbano
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Salvatore Piro
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Francesco Purrello
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
| | - Agata Maria Rabuazzo
- Department of Clinical and Molecular Medicine, University of Catania, Catania 95100, Italy.
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19
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Heiston EM, Malin SK. Impact of Exercise on Inflammatory Mediators of Metabolic and Vascular Insulin Resistance in Type 2 Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1134:271-294. [PMID: 30919343 DOI: 10.1007/978-3-030-12668-1_15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The development of obesity is cornerstone in the etiology of metabolic and vascular insulin resistance and consequently exacerbates glycemic control. Exercise is an efficacious first-line therapy for type 2 diabetes that improves insulin action through, in part, reducing hormone mediated inflammation. Together, improving the coordination of skeletal muscle metabolism with vascular delivery of glucose will be required for optimizing type 2 diabetes and cardiovascular disease treatment.
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Affiliation(s)
- Emily M Heiston
- Department of Kinesiology, University of Virginia, Charlottesville, VA, USA
| | - Steven K Malin
- Department of Kinesiology, University of Virginia, Charlottesville, VA, USA.
- Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA.
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
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20
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Zhang H, Niu Y, Gu H, Lu S, Zhang W, Li X, Yang Z, Qin L, Su Q. Low serum adiponectin is a predictor of progressing to nonalcoholic fatty liver disease. J Clin Lab Anal 2018; 33:e22709. [PMID: 30390352 DOI: 10.1002/jcla.22709] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 09/17/2018] [Accepted: 10/10/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The association between adiponectin and nonalcoholic fatty liver disease (NAFLD) has been studied before, but most of the studies are cross-sectional and cannot prove a causal link. OBJECTIVE To prospectively investigate the relationship between serum adiponectin levels and the incidence of NAFLD in 3 years. SUBJECTS AND METHODS A total of 1325 subjects aged 40 to 70 from the Chongming District of Shanghai, China, were included. All of them did not have fatty liver according to the liver ultrasound examination at entry; alcohol abuse and hepatitis were also excluded. Serum adiponectin levels and other indices were measured at baseline. After 3 years of follow-up, hepatic ultrasound examination was performed on each participant again to detect fatty liver. RESULTS The serum adiponectin levels at entry were significantly lower in subjects who developed NAFLD compared with those who did not develop NAFLD after 3 years (1.75 ± 0.89 ug/mL vs 2.37 ± 1.01 ug/mL, P < 0.001). After multiple adjustments, the highest odds ratios for NAFLD were in the second adiponectin quartile, the adjusted ORs were 1.89 (95% confidence interval [CI] 1.25 to 2.86) compared with those in the highest quartile. Multivariate logistic regression analysis showing variables at entry independently associated with NAFLD after 3 years was adiponectin (P < 0.01), sex (P < 0.01), BMI (P < 0.001), insulin (P < 0.001), HOMA-IR (P < 0.01), GGT (P = 0.001), TG (P < 0.001), and WBC (P < 0.001). CONCLUSIONS Lower serum adiponectin level is a predictor of NAFLD among middle-aged and elderly subjects.
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Affiliation(s)
- Hongmei Zhang
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Yixin Niu
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Hongxia Gu
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shuai Lu
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Weiwei Zhang
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xiaoyong Li
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Zhen Yang
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Li Qin
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Qing Su
- Department of Endocrinology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
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21
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Udomsinprasert W, Honsawek S, Poovorawan Y. Adiponectin as a novel biomarker for liver fibrosis. World J Hepatol 2018; 10:708-718. [PMID: 30386464 PMCID: PMC6206156 DOI: 10.4254/wjh.v10.i10.708] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 08/02/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023] Open
Abstract
Adiponectin is known to play primary roles in the regulation of systemic glucose homeostasis and lipid metabolism. Interestingly, emerging evidence indicates beneficial effects of adiponectin on liver fibrosis; however, the exact mechanisms of this action remain unclear. Herein, we aimed to summarize the recent findings regarding the role of adiponectin in liver fibrogenesis and update the current comprehensive knowledge regarding usefulness of adiponectin-based treatments in liver fibrosis. Adiponectin has been demonstrated to have an anti-fibrotic action in the liver by blocking the activation of hepatic stellate cell-mediated adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-alpha pathways, which in turn diminish the expression of pro-fibrotic genes. In addition, hyperadiponectinemia was noted in patients with various chronic liver diseases (CLDs)-related liver fibrosis. An increase in circulating adiponectin levels was also found to be associated with the development of liver fibrosis, indicating a role of adiponectin as a non-invasive biomarker for predicting the progression of liver fibrosis. It is therefore reasonable to speculate that adiponectin may be developed as a new therapeutic candidate for the treatment of liver fibrosis. Nonetheless, future observations are still necessary to fully elucidate the extent of the effects of adiponectin on liver fibrotic outcomes, in order to modify adiponectin as an anti-fibrotic therapy that would speed up fibrosis reversal in patients with CLD.
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Affiliation(s)
- Wanvisa Udomsinprasert
- Department of Biochemistry, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Sittisak Honsawek
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand.
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22
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Jenke A, Schur R, Röger C, Karadeniz Z, Grüger M, Holzhauser L, Savvatis K, Poller W, Schultheiss HP, Landmesser U, Skurk C. Adiponectin attenuates profibrotic extracellular matrix remodeling following cardiac injury by up-regulating matrix metalloproteinase 9 expression in mice. Physiol Rep 2018; 5:5/24/e13523. [PMID: 29263115 PMCID: PMC5742698 DOI: 10.14814/phy2.13523] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 11/05/2017] [Indexed: 01/25/2023] Open
Abstract
Adiponectin (APN) is a multifunctional adipocytokine that inhibits myocardial fibrosis, dilatation, and left ventricular (LV) dysfunction after myocardial infarction (MI). Coxsackievirus B3 (CVB3) myocarditis is associated with intense extracellular matrix (ECM) remodeling which might progress to dilated cardiomyopathy. Here, we investigated in experimental CVB3 myocarditis whether APN inhibits adverse ECM remodeling following cardiac injury by affecting matrix metalloproteinase (MMP) expression. Cardiac injury was induced by CVB3 infection in APN knockout (APN-KO) and wild-type (WT) mice. Expression and activity of MMPs was quantified by qRT-PCR and zymography, respectively. Activation of protein kinases was assessed by immunoblot. In cardiac myocytes and fibroblasts APN up-regulates MMP-9 expression via activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK)1/2 which function as master regulators of inflammation-induced MMP-9 expression. Correspondingly, APN further increased up-regulation of MMP-9 expression triggered by tumor necrosis factor (TNF)α, lipopolysaccharide (LPS) and R-848 in cardiac fibroblasts. In vivo, compared to WT mice cardiac MMP-9 activity and serum levels of carboxy-terminal telopeptide of type I collagen (ICTP) were attenuated in APN-KO mice in subacute (day 7 p.i.) CVB3 myocarditis. Moreover, on day 3 and day 7 post CVB3 infection splenic MMP-9 expression was diminished in APN-KO mice correlating with attenuated myocardial immune cell infiltration in subacute CVB3 myocarditis. These results indicate that APN attenuates adverse cardiac remodeling following cardiac injury by up-regulating MMP-9 expression in cardiac and immune cells. Thus, APN mediates intensified collagen cleavage that might explain inhibition of LV fibrosis and dysfunction.
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Affiliation(s)
- Alexander Jenke
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Robert Schur
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Carsten Röger
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Zehra Karadeniz
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Mathias Grüger
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Luise Holzhauser
- Department of Internal Medicine, Albert-Einstein College of Medicine, Bronx, New York
| | - Kostas Savvatis
- Department of Cardiology, Barts Heart Centre Barts Health NHS Trust, London, United Kingdom
| | - Wolfgang Poller
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Heinz-Peter Schultheiss
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Ulf Landmesser
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany
| | - Carsten Skurk
- Department of Cardiology, Charité University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany .,DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany
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23
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Gamberi T, Magherini F, Modesti A, Fiaschi T. Adiponectin Signaling Pathways in Liver Diseases. Biomedicines 2018; 6:biomedicines6020052. [PMID: 29735928 PMCID: PMC6027295 DOI: 10.3390/biomedicines6020052] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 04/26/2018] [Accepted: 05/02/2018] [Indexed: 02/07/2023] Open
Abstract
In the liver, adiponectin regulates both glucose and lipid metabolism and exerts an insulin-sensitizing effect. The binding of adiponectin with its specific receptors induces the activation of a proper signaling cascade that becomes altered in liver pathologies. This review describes the different signaling pathways in healthy and diseased hepatocytes, also highlighting the beneficial role of adiponectin in autophagy activation and hepatic regeneration.
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Affiliation(s)
- Tania Gamberi
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
| | - Francesca Magherini
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
| | - Alessandra Modesti
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
| | - Tania Fiaschi
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
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24
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Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Fatty Liver Disease. ZAKIM AND BOYER'S HEPATOLOGY 2018:369-390.e14. [DOI: 10.1016/b978-0-323-37591-7.00025-2] [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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25
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Abstract
PURPOSE OF REVIEW Obesity and obesity-related diseases, largely resulting from urbanization and behavioral changes, are now of global importance. Energy restriction, though, is associated with health improvements and increased longevity. We review some important mechanisms related to calorie limitation aimed at controlling of metabolic diseases, particularly diabetes. RECENT FINDINGS Calorie restriction triggers a complex series of intricate events, including activation of cellular stress response elements, improved autophagy, modification of apoptosis, and alteration in hormonal balance. Intermittent fasting is not only more acceptable to patients, but it also prevents some of the adverse effects of chronic calorie restriction, especially malnutrition. There are many somatic and potentially psychologic benefits of fasting or intermittent calorie restriction. However, some behavioral modifications related to abstinence of binge eating following a fasting period are crucial in maintaining the desired favorable outcomes.
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Affiliation(s)
- Saeid Golbidi
- Faculty of Medicine, Department of Pharmacology and Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, V6T 1Z3, Canada
| | - Andreas Daiber
- Center of Cardiology, Cardiology 1, Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Bato Korac
- Department of Physiology, Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Belgrade, Serbia
| | - Huige Li
- Department of Pharmacology, Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - M Faadiel Essop
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Ismail Laher
- Faculty of Medicine, Department of Pharmacology and Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, V6T 1Z3, Canada.
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26
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Liu X, Tong W, Zhao X, Zhang H, Tang Y, Deng X. Chinese herb extract improves liver steatosis by promoting the expression of high molecular weight adiponectin in NAFLD rats. Mol Med Rep 2017; 16:5580-5586. [PMID: 28849192 DOI: 10.3892/mmr.2017.7284] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 04/27/2017] [Indexed: 11/05/2022] Open
Abstract
High molecular weight (HMW) adiponectin (APN) is closely correlated with the development of fatty liver and is modulated by the Akt/forkhead box protein O1 (FOXO1) pathway through disulfide‑bond A oxidoreductase‑like protein (DsbA‑L). The Chinese herb extract, QSHX, is used to treat liver diseases. The present study investigated the effects of QSHX on non‑alcoholic fatty liver disease (NAFLD) and its underlying mechanism. A rat model of NAFLD was established by feeding of a high‑fat and high‑sugar diet for 20 weeks. From week 13, the rats were administered with QSHX, or saline as a control, for 8 weeks. The liver function, blood fat and plasma APN were measured using a radioimmunoassay. The hepatic tissue score was measured following staining for pathology. The expression and activities of Akt, FOXO1, DsbA‑L and HMW APN in the adipose tissue and primary adipocytes of the rats were measured using western blot analysis. It was found that QSHX significantly decreased the body weight, liver index, and serum levels of aspartate aminotransferase, alanine aminotransferase and triglyceride; and increased the serum level of APN in the NAFLD rats. Following 8 weeks of treatment with QSHX, the hepatic steatosis in the liver tissue improved and the score of hepatic steatosis was significantly decreased. The results of the western blot analysis indicated that QSHX promoted the expression of DsbA‑L and HMW APN, and reduced the expression levels of phosphorylated FOXO1 and FOXO1 in adipose tissue and primary adipocytes. It was concluded that QSHX reduced hepatic steatosis by promoting the expression of HMW APN and DsbA‑L, which may have been induced by inhibiting the activation and expression of FOXO1 in adipocytes.
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Affiliation(s)
- Xudong Liu
- Department of Liver Disease, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530011, P.R. China
| | - Wangxia Tong
- Department of Liver Disease, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530011, P.R. China
| | - Xiaofang Zhao
- Department of Liver Disease, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530011, P.R. China
| | - Hongxing Zhang
- Department of Liver Disease, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530011, P.R. China
| | - Yanfang Tang
- Department of Liver Disease, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530011, P.R. China
| | - Xin Deng
- Department of Liver Disease, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi 530011, P.R. China
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27
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Khoury T, Asombang AW, Berzin TM, Cohen J, Pleskow DK, Mizrahi M. The Clinical Implications of Fatty Pancreas: A Concise Review. Dig Dis Sci 2017; 62:2658-2667. [PMID: 28791556 DOI: 10.1007/s10620-017-4700-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 07/27/2017] [Indexed: 12/19/2022]
Abstract
Fatty pancreas is a newly recognized condition which is poorly investigated until today as compared to nonalcoholic fatty liver disease. It is characterized by pancreatic fat accumulation and subsequent development of pancreatic and metabolic complications. Association of fatty pancreas have been described with type 2 diabetes mellitus, acute and chronic pancreatitis and even pancreatic carcinoma. In this review article, we provide an update on clinical implications, pathogenesis, diagnosis, treatment and outcomes.
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Affiliation(s)
- Tawfik Khoury
- Department of Internal Medicine, Department of Gastroenterology and Liver Unit, Hadassah Hebrew University Medical Center, Ein Kerem, P.O.B. 12000, 91120, Jerusalem, Israel.
| | - Akwi W Asombang
- Division of Gastroenterology, Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
| | - Tyler M Berzin
- Division of Gastroenterology, Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
| | - Jonah Cohen
- Center of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Dana 501, Boston, MA, 02215, USA
| | - Douglas K Pleskow
- Division of Gastroenterology, Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
| | - Meir Mizrahi
- Division of Gastroenterology, Center for Advanced Endoscopy, Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis Street, Boston, MA, 02215, USA
- Division of Gastroenterology, Center for Advanced Endoscopy, University of South Alabama, Mobile, AL, USA
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28
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New insight into inter-organ crosstalk contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Protein Cell 2017. [PMID: 28643267 PMCID: PMC5818366 DOI: 10.1007/s13238-017-0436-0] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and a significant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.
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29
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Mousavi Z, Ganji A, Farrokh Tehrani D, Bahari A, EsmaeilZadeh A, Delghandi M. Correlation of visfatin level with non-alcoholic fatty liver in metabolic syndrome. Med J Islam Repub Iran 2017; 31:28. [PMID: 29445657 PMCID: PMC5804438 DOI: 10.18869/mjiri.31.28] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Indexed: 01/10/2023] Open
Abstract
Background: Metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) is a common public health problem. Visfatin is secreted by visceral adipose tissue and is an adipocytokine. It could be a pro-inflammatory adipocytokine and is related to the metabolic syndrome and non-alcoholic fatty liver disease. This study evaluated the association between visfatin levels in patients with the metabolic syndrome with and without non-alcoholic fatty liver disease (NAFLD). Methods: In this cross-sectional study, 120 patients with metabolic syndrome were selected. They were categorized into two groups, patients with fatty liver (n=70) and without fatty liver disease (n=50). Laboratory and anthropometric options such as age, sex, systolic blood pressure, fasting blood sugar, lipid profile, liver enzymes, uric acid, visfatin, insulin, BMI, waist circumference, and TNF-α were measured. The chi-square test, Mann-Whitney, t test, Spearman and Pearson correlations were used for the data analysis. Results: There was a significant difference between the fatty liver and non-fatty liver disease with visfatin, BMI, FBS and lipid profile (p<0.05). The mean±SD level of visfatin was 37.1±1.7 ng/dl in the non-fatty liver and was 44.4±1.5 ng/dl in fatty liver participants (p=0.02). 59% of patients with metabolic syndrome had fatty liver in ultrasonography. Conclusion: According to this study, there was a correlation between visfatin levels and fatty liver disease.
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Affiliation(s)
- Zohreh Mousavi
- Endocrine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Azita Ganji
- Gastroenterology and Hepatology Research Center. Mashhad University of Medical Sciences & Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Ali Bahari
- Gastroenterology and Hepatology Research Center. Mashhad University of Medical Sciences & Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abbas EsmaeilZadeh
- Gastroenterology and Hepatology Research Center. Mashhad University of Medical Sciences & Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Delghandi
- Gastroenterology and Hepatology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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30
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Neuman MG, French SW, Zakhari S, Malnick S, Seitz HK, Cohen LB, Salaspuro M, Voinea-Griffin A, Barasch A, Kirpich IA, Thomes PG, Schrum LW, Donohue TM, Kharbanda KK, Cruz M, Opris M. Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage. Exp Mol Pathol 2017; 102:162-180. [PMID: 28077318 DOI: 10.1016/j.yexmp.2017.01.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 01/04/2017] [Indexed: 02/06/2023]
Abstract
This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | | | | | - Stephen Malnick
- Department Internal Medicine, Kaplan Medical Centre and Hebrew University of Jerusalem, Rehovot, Israel
| | - Helmut K Seitz
- Centre of Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Lawrence B Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Mikko Salaspuro
- Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland
| | - Andreea Voinea-Griffin
- Public Health Science Texas A&M University, College of Dentistry, Dallas University, TX, USA
| | - Andrei Barasch
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Paul G Thomes
- Department of Internal Medicine, Carolinas Medical Center, Charlotte, NC, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Laura W Schrum
- Department of Internal Medicine, Carolinas Medical Center, Charlotte, NC, USA
| | - Terrence M Donohue
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kusum K Kharbanda
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Marcus Cruz
- In Vitro Drug Safety and Biotechnology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Mihai Opris
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Family Medicine Clinic CAR, Bucharest, Romania
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31
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Ohmi S, Ono M, Takata H, Hirano S, Funakoshi S, Nishi Y, Yoshimura K, Amano E, Terada Y, Saibara T, Fujimoto S. Analysis of factors influencing glucose tolerance in Japanese patients with non-alcoholic fatty liver disease. Diabetol Metab Syndr 2017; 9:65. [PMID: 28878826 PMCID: PMC5584018 DOI: 10.1186/s13098-017-0264-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 08/28/2017] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND While the association of the prevalence of non-alcoholic fatty liver disease (NAFLD) with impaired glucose metabolism has been reported, the factors influencing glucose tolerance in NAFLD remain to be clarified. METHODS Glucose tolerance of 131 Japanese patients diagnosed as NAFLD by histological findings of liver biopsy specimen was examined using 75 g-OGTT. According to Matteoni's classification, patients were divided to 4 groups [M1 ~ 4, M1, 2: non-alcoholic fatty liver (NAFL); and M3, 4: non-alcoholic steatohepatitis (NASH)]. Based on the OGTT data, insulinogenic index (IGI) and QUICKI were calculated as indices of insulin secretion and insulin sensitivity, respectively. Plasma glucose 120 min after glucose loading (G120) was used as the index for glucose intolerance. RESULTS Stepwise multiple regression analysis using G120 as a dependent variable and loge-IGI, QUICKI, sex, BMI, age, NAFL/NASH as independent variables revealed that loge-IGI (β = -0.595) and QUICKI (β = -0.323) are significant factors predicting glucose intolerance (R2 = 0.403), indicating an important role of insulin secretion in glucose tolerance. These findings accord with glucose intolerance as high as 89.7% in patients with impaired insulin secretion defined by ≤43.2 pmol/mmol (40 μU/mg) IGI. Stepwise multiple regression analysis using QUICKI as a dependent variable and NAFL/NAFLD, sex, BMI, and age as independent variables revealed that BMI (β = -0.469) and NAFL/NAFLD (β = -0.204) are significant factors predicting insulin sensitivity (R2 = 0.248). CONCLUSION Impairment of insulin secretion is the most important factor to predict glucose intolerance in NAFLD; severity of histological findings is associated with insulin sensitivity independent of adiposity in NAFLD.
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Affiliation(s)
- Satoko Ohmi
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Masafumi Ono
- Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Hiroshi Takata
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Seiki Hirano
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Shogo Funakoshi
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Yuichi Nishi
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Kumiko Yoshimura
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Eri Amano
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Yoshio Terada
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Toshiji Saibara
- Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
| | - Shimpei Fujimoto
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku, Kochi 783-8505 Japan
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Oh KJ, Lee DS, Kim WK, Han BS, Lee SC, Bae KH. Metabolic Adaptation in Obesity and Type II Diabetes: Myokines, Adipokines and Hepatokines. Int J Mol Sci 2016; 18:ijms18010008. [PMID: 28025491 PMCID: PMC5297643 DOI: 10.3390/ijms18010008] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/24/2016] [Accepted: 12/12/2016] [Indexed: 12/21/2022] Open
Abstract
Obesity and type II diabetes are characterized by insulin resistance in peripheral tissues. A high caloric intake combined with a sedentary lifestyle is the leading cause of these conditions. Whole-body insulin resistance and its improvement are the result of the combined actions of each insulin-sensitive organ. Among the fundamental molecular mechanisms by which each organ is able to communicate and engage in cross-talk are cytokines or peptides which stem from secretory organs. Recently, it was reported that several cytokines or peptides are secreted from muscle (myokines), adipose tissue (adipokines) and liver (hepatokines) in response to certain nutrition and/or physical activity conditions. Cytokines exert autocrine, paracrine or endocrine effects for the maintenance of energy homeostasis. The present review is focused on the relationship and cross-talk amongst muscle, adipose tissue and the liver as secretory organs in metabolic diseases.
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Affiliation(s)
- Kyoung-Jin Oh
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
| | - Da Som Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
| | - Won Kon Kim
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
| | - Baek Soo Han
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
| | - Sang Chul Lee
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
| | - Kwang-Hee Bae
- Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea.
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Yamamoto H, Nakae H, Uji Y, Maeda K, Tani T, Eguchi Y. Plasma Adiponectin Levels in Acute Liver Failure Patients Treated with Plasma Filtration with Dialysis and Plasma Exchange. Ther Apher Dial 2016; 19:349-54. [PMID: 26386223 DOI: 10.1111/1744-9987.12344] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Plasma filtration with dialysis (PDF) is a blood purification therapy in which simple plasma exchange (PE) is performed using a selective membrane plasma separator while the dialysate flows outside of the hollow fibers. Improvement of hypoadiponectinemia is considered to be a useful therapeutic approach for ameliorating fatal conditions including cardio-metabolic and infectious disease. We investigated the effects of PDF in comparison to PE in terms of plasma adiponectin (APN) changes in patients with acute liver failure. Seventeen patients with liver failure were studied; PDF was performed 55 times and PE 14 times. Plasma APN levels increased significantly after PDF, while decreasing significantly after PE. PDF appears to be among the most useful blood purification therapies in acute liver failure cases in terms of increasing APN levels.
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Affiliation(s)
- Hiroshi Yamamoto
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Hajime Nakae
- Department of Emergency and Critical Care Medicine, Akita University School of Medicine, Akita, Japan
| | - Yoshitaka Uji
- Department of Gastroenterological Surgery, Shinkoga Hospital, Fukuoka, Japan
| | - Kazuhisa Maeda
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tohru Tani
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Yutaka Eguchi
- Department of Critical and Intensive Care Medicine, Shiga University of Medical Science, Shiga, Japan
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Jamali R, Razavizade M, Arj A, Aarabi MH. Serum adipokines might predict liver histology findings in non-alcoholic fatty liver disease. World J Gastroenterol 2016; 22:5096-5103. [PMID: 27275102 PMCID: PMC4886385 DOI: 10.3748/wjg.v22.i21.5096] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 02/25/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To assess significance of serum adipokines to determine the histological severity of non-alcoholic fatty liver disease. METHODS Patients with persistent elevation in serum aminotransferase levels and well-defined characteristics of fatty liver at ultrasound were enrolled. Individuals with a history of alcohol consumption, hepatotoxic medication, viral hepatitis or known liver disease were excluded. Liver biopsy was performed to confirm non-alcoholic liver disease (NAFLD). The degrees of liver steatosis, lobular inflammation and fibrosis were determined based on the non-alcoholic fatty liver activity score (NAS) by a single expert pathologist. Patients with a NAS of five or higher were considered to have steatohepatitis. Those with a NAS of two or lower were defined as simple fatty liver. Binary logistic regression was used to determine the independent association of adipokines with histological findings. Receiver operating characteristic (ROC) analysis was employed to determine cut-off values of serum adipokines to discriminate the grades of liver steatosis, lobular inflammation and fibrosis. RESULTS Fifty-four participants aged 37.02 ± 9.82 were enrolled in the study. Higher serum levels of visfatin, IL-8, TNF-α levels were associated independently with steatosis grade of more than 33% [β = 1.08 (95%CI: 1.03-1.14), 1.04 (95%CI: 1.008-1.07), 1.04 (95%CI: 1.004-1.08), P < 0.05]. Elevated serum IL-6 and IL-8 levels were associated independently with advanced lobular inflammation [β = 1.4 (95%CI: 1.09-1.8), 1.07 (95%CI: 1.003-1.15), P < 0.05]. Similarly, higher TNF-α, resistin, and hepcidin levels were associated independently with advanced fibrosis stage [β = 1.06 (95%CI: 1.002-1.12), 19.86 (95%CI: 2.79-141.19), 560.72 (95%CI: 5.98-5255.33), P < 0.05]. Serum IL-8 and TNF-α values were associated independently with the NAS score, considering a NAS score of 5 as the reference value [β = 1.05 (95%CI: 1.01-1.1), 1.13 (95%CI: 1.04-1.22), P < 0.05]. CONCLUSION Certain adipokines may determine the severity of NAFLD histology accurately.
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Kanwar P, Kowdley KV. The Metabolic Syndrome and Its Influence on Nonalcoholic Steatohepatitis. Clin Liver Dis 2016; 20:225-43. [PMID: 27063266 DOI: 10.1016/j.cld.2015.10.002] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) and the metabolic syndrome (MetS) are highly prevalent in the Western population. Their pathogenesis is closely linked to insulin resistance, which serves as a therapeutic target for the management of these conditions. This review article reviews the research supporting the influence of MetS on NASH and includes studies supporting their similar epidemiology, pathogenesis, and treatment.
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Affiliation(s)
- Pushpjeet Kanwar
- Department of Gastroenterology and Hepatology, New York Methodist Hospital, 506, 6th Street, Brooklyn, NY 11215, USA
| | - Kris V Kowdley
- Department of Transplant Hepatology, Swedish Medical Center, 1101, Madison Street, Suite 200, Seattle, WA 98104, USA.
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Fotbolcu H, Zorlu E. Nonalcoholic fatty liver disease as a multi-systemic disease. World J Gastroenterol 2016; 22:4079-4090. [PMID: 27122660 PMCID: PMC4837427 DOI: 10.3748/wjg.v22.i16.4079] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/02/2016] [Accepted: 03/02/2016] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD includes a wide spectrum of liver conditions ranging from simple steatosis to nonalcoholic steatohepatitis and advanced hepatic fibrosis. NAFLD has been recognized as a hepatic manifestation of metabolic syndrome linked with insulin resistance. NAFLD should be considered not only a liver specific disease but also an early mediator of systemic diseases. Therefore, NAFLD is usually associated with cardiovascular disease, chronic kidney disease, type 2 diabetes, obesity, and dyslipidemia. NAFLD is highly prevalent in the general population and is associated with increased cardiovascular morbidity and mortality. The underlying mechanisms and pathogenesis of NAFLD with regard to other medical disorders are not yet fully understood. This review focuses on pathogenesis of NAFLD and its relation with other systemic diseases.
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Højland Ipsen D, Tveden-Nyborg P, Lykkesfeldt J. Normal weight dyslipidemia: Is it all about the liver? Obesity (Silver Spring) 2016; 24:556-67. [PMID: 26868960 DOI: 10.1002/oby.21443] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 09/02/2015] [Accepted: 11/30/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The liver coordinates lipid metabolism and may play a vital role in the development of dyslipidemia, even in the absence of obesity. Normal weight dyslipidemia (NWD) and patients with nonalcoholic fatty liver disease (NAFLD) who do not have obesity constitute a unique subset of individuals characterized by dyslipidemia and metabolic deterioration. This review examined the available literature on the role of the liver in dyslipidemia and the metabolic characteristics of patients with NAFLD who do not have obesity. METHODS PubMed was searched using the following keywords: nonobese, dyslipidemia, NAFLD, NWD, liver, and metabolically obese/unhealthy normal weight. Additionally, article bibliographies were screened, and relevant citations were retrieved. Studies were excluded if they had not measured relevant biomarkers of dyslipidemia. RESULTS NWD and NAFLD without obesity share a similar abnormal metabolic profile. When compared with patients with NAFLD who have obesity, the metabolic abnormalities of NAFLD without obesity are similar or less severe. Furthermore, hepatic lesions develop independent of obesity, and the extent of dyslipidemia seems comparable. CONCLUSIONS NAFLD may impair hepatic lipid handling, causing faulty lipid homeostasis, and serves as a likely starting point for initiation and propagation of dyslipidemia along with associated comorbidities in patients without obesity.
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Affiliation(s)
- David Højland Ipsen
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Pernille Tveden-Nyborg
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Bekaert M, Verhelst X, Geerts A, Lapauw B, Calders P. Association of recently described adipokines with liver histology in biopsy-proven non-alcoholic fatty liver disease: a systematic review. Obes Rev 2016; 17:68-80. [PMID: 26597657 DOI: 10.1111/obr.12333] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 09/11/2015] [Indexed: 12/25/2022]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising, as is the prevalence of obesity and type 2 diabetes. It is increasingly recognized that an impaired pattern in adipokine secretion could play a pivotal role in the development of NAFLD. We performed a systematic review to evaluate the potential link between newly described adipokines and liver histology in biopsy-proven NAFLD patients. A computerized literature search was performed in PubMed, EMBASE and Web of Science electronic databases. Thirty-one cross-sectional studies were included, resulting in a total of seven different investigated adipokines. Studies included in this review mainly had a good methodological quality. Most adipokines were suggested to be involved in the inflammatory response that develops within the context of NAFLD, either at hepatic or systemic level, and/or hepatic insulin resistance. Based on literature, clinical studies suggest that chemerin, resistin and adipocyte-fatty-acid-binding protein potentially are involved in NAFLD pathogenesis and/or progression. However, major inconsistency still exists, and there is a high need for larger studies, together with the need of standardized assays to determine adipokine levels.
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Affiliation(s)
- M Bekaert
- Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - X Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - A Geerts
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - B Lapauw
- Department of Endocrinology, Ghent University Hospital, Ghent, Belgium
| | - P Calders
- Revalidation Science and Physiotherapy, Ghent University Hospital, Ghent, Belgium
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Cengiz M, Ozenirler S, Kocabiyik M. Serum β-trophin level as a new marker for noninvasive assessment of nonalcoholic fatty liver disease and liver fibrosis. Eur J Gastroenterol Hepatol 2016; 28:57-63. [PMID: 26513612 DOI: 10.1097/meg.0000000000000502] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease and evaluation of fibrosis is important. We aimed to investigate the utility of serum β-trophin in NAFLD and its ability to predict liver fibrosis. PATIENTS AND METHODS Serum samples of consecutive patients with biopsy-proven NAFLD and age-matched and sex-matched healthy controls were used to measure β-trophin using ELISA. Correlations between histopathological features of NAFLD and β-trophin were analyzed. Whereas patients with fibrosis scores less than 2 were grouped in the mild fibrosis group, patients with scores of 2 or more were grouped in the significant fibrosis group. Univariate/multivariate logistic regression analyses were carried out to evaluate the independent predicting factors of liver fibrosis. Receiver operating characteristics (ROCs) were assessed to determine the best cut-off values for NAFLD and fibrosis. RESULTS Sixty-nine patients with NAFLD and 69 healthy controls were enrolled in the study. Serum β-trophin levels were lower in NAFLD patients compared with the controls (2.34±0.06 vs. 1.94±0.09 ng/ml, respectively, P<0.001). In NAFLD, serum β-trophin was related to liver fibrosis and inflammation. The mild fibrosis group had higher serum β-trophin levels than the significant fibrosis group (2.11±0.12 vs. 1.72±0.11, respectively, P<0.001). In multivariate analysis, β-trophin remained an independent predictor of significant fibrosis (odds ratio, 0.237; 95% confidence interval, 0.059-0.949; P<0.001). ROC analysis showed that serum β-trophin was statistically significant in the identification of significant fibrosis (area under receiver operating characteristic, 0.844; 95% confidence interval, 0.718-0.970; P<0.001). The best cut-off value was 1.786, with the best sensitivity (71.43%) and specificity (95.65%). CONCLUSION Serum β-trophin may be a potential noninvasive marker for the identification of NAFLD and significant liver fibrosis.
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Affiliation(s)
- Mustafa Cengiz
- aDepartment of Gastroenterology, Dr. A.Y. Ankara Oncology Training and Research Hospital bDepartment of Gastroenterology cDepartment of Biochemistry, Faculty of Medicine, Gazi University, Ankara, Turkey
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Della Corte C, Mosca A, Majo F, Lucidi V, Panera N, Giglioni E, Monti L, Stronati L, Alisi A, Nobili V. Nonalcoholic fatty pancreas disease and Nonalcoholic fatty liver disease: more than ectopic fat. Clin Endocrinol (Oxf) 2015. [PMID: 26201937 DOI: 10.1111/cen.12862] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the metabolic effects of fatty pancreas (nonalcoholic fatty pancreas disease - NAFPD) in a group of obese paediatric patients with nonalcoholic fatty liver disease (NAFLD). METHODS We included 121 consecutive children with echographic evidence of hepatic steatosis. All patients underwent to abdominal ultrasound to evaluate pancreatic echogenic pattern. We divided the patients into two groups on the basis of the presence of fatty pancreas. In all patients liver function tests, lipid and gluco-insulinemic profile were evaluated. A selected subset of patients (67) underwent to liver biopsy. RESULTS Of these 121 patients, 58 showed NAFPD and 63 patients exhibited a normal pancreatic echogenic pattern. No differences were found in age, transaminases serum levels, lipid profile and pancreatic enzymes between the two groups. The patients with NAFPD had a significantly higher z-BMI, fasting insulin, insulin resistance (HOMA-IR) and lower ISI respect to the group without fatty pancreas. The patients with fatty pancreas showed a more advanced form of liver disease, with higher values of fibrosis, ballooning and NAS score with respect to the group without NAFPD. CONCLUSIONS Our study demonstrated that NAFPD is a frequent condition in obese paediatric patients affected by NAFLD. Our data suggest that pancreatic fat should not be considered an inert accumulation of fat, but as an additional factor able to affect glucose metabolism and severity of liver disease, increasing the risk of develop metabolic syndrome.
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Affiliation(s)
- C Della Corte
- Hepato-Metabolic Department, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
| | - A Mosca
- Hepato-Metabolic Department, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
| | - F Majo
- Cystic Fibrosis Unit, Pediatric Department, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
| | - V Lucidi
- Cystic Fibrosis Unit, Pediatric Department, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
| | - N Panera
- Liver Research Unit, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
| | - E Giglioni
- Emergency Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - L Monti
- Liver and Digestive Radiology Unit, Department of Imaging, Bambino Gesu' Children's Hospital, IRCCS, Rome, Italy
| | - L Stronati
- Institute of Biology, Molecular Medicine and Nanobiotechnology, CNR, Rome, Italy
| | - A Alisi
- Liver Research Unit, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
| | - V Nobili
- Hepato-Metabolic Department, 'Bambino Gesù' Children's Hospital, IRCCS, Rome, Italy
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Adiponectin as an anti-fibrotic and anti-inflammatory adipokine in the liver. CURRENT PATHOBIOLOGY REPORTS 2015; 3:243-252. [PMID: 26858914 DOI: 10.1007/s40139-015-0094-y] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic fibrosis is a dynamic process resulting from excessive deposition of extracellular matrix in the liver; uncontrolled progression of fibrosis can eventually lead to liver cirrhosis and/or hepatocellular carcinoma. The fibrogenic process is complex and modulated by a number of both hepatic and extra-hepatic biological factors. Growing evidence indicates that adipokines, a group of cytokines produced by adipose tissue, impart dynamic functions in liver and are involved in modulation of hepatic fibrosis. In particular, two key adipokines, adiponectin and leptin, directly regulate many biological responses closely associated with development and progression of hepatic fibrosis. Leptin acts as a pro-fibrogenic cytokine, while adiponectin possesses anti-fibrogenic and anti-inflammatory properties. Adiponectin, acting via its cognate receptors, adiponectin receptors 1 and 2, potently suppresses fibrosis and inflammation in liver via multiple mechanisms. This review summarizes recent findings concerning the role of adiponectin in fibrogenic process in liver and addresses the underlying molecular mechanisms in modulation of fibrosis.
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Siddiqui MS, Cheang KL, Luketic VA, Boyett S, Idowu MO, Patidar K, Puri P, Matherly S, Stravitz RT, Sterling RK, Sanyal AJ. Nonalcoholic Steatohepatitis (NASH) Is Associated with a Decline in Pancreatic Beta Cell (β-Cell) Function. Dig Dis Sci 2015; 60:2529-37. [PMID: 25784075 PMCID: PMC4900167 DOI: 10.1007/s10620-015-3627-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 03/03/2015] [Indexed: 12/28/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) represents a histological spectrum ranging from benign hepatic steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD is closely associated with insulin resistance (IR), and although the role of IR in NAFLD has been an area of intense investigation, there are limited data on pancreatic β-cell function. AIM To evaluate the pancreatic β-cell function in NAFLD using the homeostatic model assessment-β (HOMA-β) and β-cell index (BI). METHODS HOMA-β was measured in ninety-nine non-diabetic subjects with histologically confirmed NAFLD and compared to lean (age- and gender-matched) and obese (age-, gender-, and BMI-matched) controls. Using the values from an oral glucose tolerance test, BI was compared in 31 non-diabetic, non-cirrhotic subjects with NASH and gender- and BMI-matched controls. RESULTS The subjects with NAFLD had higher HOMA-β compared to both lean and obese controls (43.1 vs. 9 vs. 22.1 %, respectively, P < 0.05). HOMA-β was directly related to serum alkaline phosphate, total bilirubin, and weight and inversely related to age. There was no difference in HOMA-β between subjects with NAFL and NASH. Subjects with NASH had lower β-cell function as measured by a lower BI (2.09 ± 1.64 vs. 7.74 ± 25.12; P = 0.04). In patients with NASH, BI was inversely associated with fibrosis independent of age, BMI, and serum ALT levels. In contrast, HOMA-β was directly associated with fibrosis stage. CONCLUSION NASH is associated with strained pancreatic β-cell function in non-diabetic subjects. Future studies are necessary to evaluate the temporal relationship between β-cell function and hepatic histology.
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Affiliation(s)
- Mohamed S. Siddiqui
- Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Kai L. Cheang
- Division of Endocrinology, Dept. of Internal Medicine, Virginia Commonwealth University
| | - Velimir A. Luketic
- Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Sherry Boyett
- Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Michael O. Idowu
- Div. of Surgical Pathology, Dept. of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | | | - Puneet Puri
- Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Scott Matherly
- Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Richard T. Stravitz
- Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Richard K. Sterling
- Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
| | - Arun J. Sanyal
- Div. of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
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Chatterjee R, Mitra A. An overview of effective therapies and recent advances in biomarkers for chronic liver diseases and associated liver cancer. Int Immunopharmacol 2015; 24:335-345. [PMID: 25560752 DOI: 10.1016/j.intimp.2014.12.024] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 12/12/2014] [Accepted: 12/14/2014] [Indexed: 02/07/2023]
Abstract
Chronic liver diseases (CLDs) such as hepatitis, alcoholic liver disease, nonalcoholic fatty liver, and their downstream effect cancer affect more than a billion of people around the world both symptomatically and asymptomatically. The major limitation for early detection and suitable medical management of CLDs and liver cancer is either the absent of symptoms or their similar manifestations as other diseases. This detection impediment has led to a steady increase in the number of people suffering from CLDs with an ultimate outcome of liver failure and undergoing transplantation. A better understanding of CLD pathogenesis has helped us to develop novel therapies for patients who are at greatest risk for CLD progression to the most serious disease cancer. With the discovery of aberrant molecular pathways in CLDs, it is now possible to delineate a road map for selecting targeted therapies for CLDs. Technological advances in imaging as well as the availability of several stable, sensitive, early, noninvasive biomarkers for distinguishing different stages of CLDs and cancer have greatly facilitated both drug target identification and real-time monitoring of response to therapy. Biomarkers are the most useful in clinical practice for liver diseases like hepatocellular carcinoma (HCC), which is associated with secretion of various tumor-related proteins or nucleotides in peripheral circulation. The need for the identification of CLD biomarkers remains high. This article reviews the etiologies of CLDs, the results of recent clinical trials of treatments for CLDs, and development of noninvasive methodologies for detecting CLDs and monitoring their progression toward HCC.
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Affiliation(s)
| | - Abhisek Mitra
- University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Lin Z, Wu F, Lin S, Pan X, Jin L, Lu T, Shi L, Wang Y, Xu A, Li X. Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice. J Hepatol 2014; 61:825-31. [PMID: 24882054 DOI: 10.1016/j.jhep.2014.05.033] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 05/02/2014] [Accepted: 05/22/2014] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Acetaminophen (APAP) overdose causes hepatic necrosis and acute liver injury by inducing mitochondrial dysfunction and damage. Although the biochemical pathways that mediate APAP-induced hepatotoxicity have been well studied, the body's defense mechanism to attenuate this disease remains elusive. This study investigated the roles of adiponectin, an adipocyte-secreted adipokine with pleiotropic protective effects against obesity-related metabolic dysfunction, in the pathogenesis of APAP-induced liver injury in mice. METHODS Adiponectin knockout (ADN KO) and C57 wild type mice were treated with an overdose of APAP, followed by histological and biochemical evaluation of liver injury and activation of autophagy. The mechanism of adiponectin in APAP-induced hepatocytic toxicity was also explored in primary cultured hepatocytes. RESULTS APAP overdose triggers a marked accumulation of adiponectin in injured liver tissues. ADN KO mice exhibit severely exacerbated mitochondrial dysfunction and damage, oxidative stress and necrosis and much higher mortality in response to APAP overdose, whereas these changes are reversed by a single injection of adiponectin. Mechanistically, adiponectin induces autophagosome formation by AMP-activated protein kinase (AMPK)-dependent activation of the Unc-51-like kinase 1, consequently leading to the removal of damaged mitochondria from hepatocytes. The protective effects of adiponectin against APAP-induced mitochondrial damage, oxidative stress and necrosis are abrogated by blockage of AMPK or pharmacological inhibition of autophagy. CONCLUSIONS Our findings suggest that the APAP-induced accumulation of adiponectin in liver tissues serves as an adaptive mechanism to ameliorate hepatotoxicity by promoting autophagy-mediated clearance of damaged mitochondria. Adiponectin agonists may represent a promising therapy for the drug-induced acute liver failure.
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Affiliation(s)
- Zhuofeng Lin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Fan Wu
- Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Shaoqiang Lin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Xuebo Pan
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Leigang Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Tingting Lu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Lihua Shi
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Yu Wang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China; Department of Medicine, The University of Hong Kong, Hong Kong, China; Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
| | - Xiaokun Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China; Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China.
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Cohen M, Syme C, Deforest M, Wells G, Detzler G, Cheng HL, McCrindle B, Hanley A, Hamilton J. Ectopic fat in youth: the contribution of hepatic and pancreatic fat to metabolic disturbances. Obesity (Silver Spring) 2014; 22:1280-6. [PMID: 24402863 DOI: 10.1002/oby.20674] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 11/15/2013] [Accepted: 11/30/2013] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To study the relationships between parameters of glucose and insulin metabolism and visceral and abdominal ectopic fat in youth. METHODS A cross sectional study of 50 children (24 females), 8-18 years old. Anthropometrics, body composition, blood-work and visceral and ectopic fat by magnetic resonance imaging were assessed. Insulin secretion, insulin sensitivity and beta cell function were calculated from an oral glucose tolerance test. RESULTS BMI z-scores ranged between -1.3 and 4.5. The hepatic fat fraction (HFF) ranged between 0 and 36% and pancreatic fat fraction (PFF) between 0 and 14%. Visceral fat, HFF and PFF were associated with clinical and biochemical metabolic abnormalities, and correlated with markers of insulin sensitivity (r = -0.60, P < 0.01; r = -0.64, P < 0.01; r = -0.48, P < 0.01, respectively) insulin secretion (r = 0.55, P < 0.01; r = 0.57, P < 0.01; r = 0.41, P < 0.01, respectively), and beta cell function (r = -0.49, P < 0.01; r = -0.59, P < 0.01; r = -0.39, P < 0.01, respectively). CONCLUSIONS Accumulations of pancreatic and hepatic fat have complementary clinical consequences in youth. While visceral and hepatic fat demonstrated a dominant effect, even relatively small degrees of pancreatic fat deposition may contribute to metabolic alterations.
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Affiliation(s)
- Michal Cohen
- Division of Endocrinology, the Hospital for Sick Children, and the University of Toronto, ON, Canada
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Ferreira DMS, Simão AL, Rodrigues CMP, Castro RE. Revisiting the metabolic syndrome and paving the way for microRNAs in non-alcoholic fatty liver disease. FEBS J 2014; 281:2503-24. [PMID: 24702768 DOI: 10.1111/febs.12806] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Revised: 03/16/2014] [Accepted: 04/03/2014] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of stages from simple steatosis to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and, ultimately, hepatocellular carcinoma. Despite being one of the most common chronic liver diseases, NAFLD pathogenesis remains largely unknown. In this review, we discuss the key molecular mechanisms involved in NAFLD development and progression, focusing on the emerging role of microRNAs. NAFLD is intrinsically related to obesity and the metabolic syndrome. Changes in lipid metabolism increase free fatty acids in blood, which in turn induces peripheral insulin resistance and increases oxidative and endoplasmic reticulum stress. Although not yet considered in the diagnosis of NAFLD, recent reports also reinforce the crucial role of apoptosis in disease progression via activation of either death receptor or mitochondrial pathways and p53. In addition, the role of gut microbiota and the gut-liver axis has been recently associated with NAFLD. Finally, there is an accumulating and growing body of evidence supporting the role of microRNAs in NAFLD pathogenesis and progression, as well as hinting at their use as biomarkers or therapeutic tools. The ultimate goal is to review different molecular pathways that may underlie NAFLD pathogenesis in the hope of finding targets for new and efficient therapeutic interventions.
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Affiliation(s)
- Duarte M S Ferreira
- Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
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Silva TE, Colombo G, Schiavon LL. Adiponectin: A multitasking player in the field of liver diseases. DIABETES & METABOLISM 2014; 40:95-107. [PMID: 24486145 DOI: 10.1016/j.diabet.2013.11.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 11/19/2013] [Accepted: 11/21/2013] [Indexed: 12/18/2022]
Abstract
Adiponectin is the most abundant adipokine synthesized by adipose tissue and has been shown to be a key component in the relationship between adiposity, insulin resistance and inflammation. It circulates in plasma at physiological concentrations that represent 0.05% of all plasma proteins. Adiponectin has trimeric, hexameric and multimeric forms that bind to receptors AdipoR1, AdipoR2 and T-cadherin especially in liver, muscle and endothelial cells. Adiponectin is considered a potent modulator of lipid and glucose metabolism with antidiabetic, antiatherogenic and anti-inflammatory properties, and plays an important role in the pathogenesis of metabolic diseases. The hepatoprotective effects of adiponectin, especially in non-alcoholic fatty liver disease (NAFLD), have been widely investigated, and its antisteatotic, anti-inflammatory and antifibrogenic effects have already been described. Adiponectin levels are reduced in individuals with fatty liver disease independently of body mass index, insulin resistance and other adipokines, and are inversely related to the severity of steatosis and necroinflammation, suggesting an important role in the relationship between adipose tissue, the liver and insulin sensitivity. Adiponectin has also been found to be reduced in cases of hepatitis B and C infection, and in cholestatic and autoimmune diseases, but is increased in patients with cirrhosis of different aetiologies. In addition, an important role for the liver in the regulation of adiponectin secretion by adipocytes, mediated by bile acids, has recently been proposed. The present report describes the importance of adiponectin in hepatic diseases as well as some future perspectives of the role of adiponectin as a biomarker and therapeutic target in liver diseases.
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Affiliation(s)
- T E Silva
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970.
| | - G Colombo
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970
| | - L L Schiavon
- Division of Gastroenterology, Federal University of Santa Catarina Campus, Universitário Reitor João David Ferreira Lima, Trindade Florianópolis, SC, Brazil 88040970
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Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des 2014; 19:5219-38. [PMID: 23394097 PMCID: PMC3850262 DOI: 10.2174/13816128113199990381] [Citation(s) in RCA: 162] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 02/01/2013] [Indexed: 02/07/2023]
Abstract
Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.
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Affiliation(s)
- Paola Dongiovanni
- Department of Pathophysiology and Transplantation, section Internal Medicine, Università degli Studi Milano, UO Medicina Interna1B, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Abstract
Fatty liver is a growing health problem worldwide. It might evolve to nonalcoholic steatohepatitis, cirrhosis and cause hepatocellular carcinoma. This disease, which has increased because of eating habits, changes in food content and lifestyle, affects people from childhood. The most important risk factors are obesity and insulin resistance. Besides these factors, gender, ethnicity, genetic predisposition and some medical problems are also important. Cirrhosis in children is rare but is reported. Nonalcoholic fatty liver disease (NAFLD) has no specific symptoms or signs but should be considered in obese children. NAFLD does not have a proven treatment. Weight loss with family based treatments is the most acceptable management. Exercise and an applicable diet with low glycemic index and appropriate calorie intake are preferred. Drugs are promising but not sufficient in children for today.
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Baranova A, Randhawa M, Jarrar M, Younossi ZM. Adipokines and melanocortins in the hepatic manifestation of metabolic syndrome: nonalcoholic fatty liver disease. Expert Rev Mol Diagn 2014; 7:195-205. [PMID: 17331066 DOI: 10.1586/14737159.7.2.195] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Metabolic syndrome is associated with nonalcoholic fatty liver disease and its more aggressive form, nonalcoholic steatohepatitis. Adipokines produced by white adipose tissue possess broad physiological activity and play an important autocrine role in obesity-associated complications, including metabolic syndrome, nonalcoholic fatty liver disease and cardiovascular disease. Various adipokines may have beneficial or harmful effects. Other tissues, particularly stomach and intestine, produce active molecules that can influence the function of adipocytes and, possibly, the levels of adipokine secretion. In some cases, the production sites of these molecules remain unknown. The review focuses on our current understanding of the disease-related effects of the adipokines and the melanocortins on various peripheral tissues, and discusses some of their potential interactions with each other. Potential therapeutic applications are also considered.
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Affiliation(s)
- Ancha Baranova
- Center for Liver Diseases, Inova Fairfax Hospital, VA, USA.
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