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      Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects

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          Abstract

          Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a significant liver disease, and it covers the disease spectrum from simple steatosis with a risk of development of non-alcoholic steatohepatitis (NASH) to fibrosis, subsequent cirrhosis, end-stage liver failure, and liver cancer with a potential need for liver transplantation. NAFLD and NASH are closely related to obesity, metabolic syndrome, and type 2 diabetes (T2D). The role of gut hormones, especially glucagon-like peptide 1 (GLP-1), is important in NAFLD. Bariatric surgery has the potential for inducing great weight loss and may improve the symptoms of metabolic syndrome and T2D. Recent data demonstrated significant effects of bariatric surgery on GLP-1 and other gut hormones and important lipid metabolic and inflammatory abnormalities in the pathophysiology of NAFLD. Therefore, bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients. In the present review, we describe NAFLD and NASH pathophysiology and the primary effects of bariatric surgery on metabolic pathways. We performed a systematic review of the beneficial and harmful effects and focused on changes in liver disease severity in NAFLD and NASH patients. The specific focus was liver histopathology as assessed by the invasive liver biopsy. Additionally, we reviewed several non-invasive methods used for the assessment of liver disease severity following bariatric surgery.

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          Most cited references63

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          Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

          Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; I148M) was strongly associated with increased hepatic fat levels (P=5.9×10−10) and with hepatic inflammation (P=3.7×10−4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.
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            Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

            Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease. To elucidate the molecular basis of NAFLD we performed an exome-wide association study of liver fat content. Three variants were associated with increased liver fat at the exome-wide significance level: two in PNPLA3, an established locus for NAFLD, and one (Glu167Lys) in TM6SF2, a gene of unknown function. The Glu167LysTM6SF2 variant was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and lower levels of LDL-cholesterol, triglycerides and alkaline phosphatase in 3 independent populations (n>80,000). Recombinant Glu167LysTM6SF2 produced 50% less protein than wild-type TM6SF2 when expressed in cultured hepatocytes. Adeno-associated virus-mediated shRNA knockdown of Tm6sf2 in mice increased liver triglyceride content 3-fold and decreased VLDL secretion by 50%. Taken together, these data indicate that TM6SF2 activity is required for normal VLDL secretion, and that impaired TM6SF2 function causally contributes to NAFLD.
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              Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes.

              The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.

                Author and article information

                Contributors
                Journal
                World J Hepatol
                WJH
                World Journal of Hepatology
                Baishideng Publishing Group Inc
                1948-5182
                27 February 2019
                27 February 2019
                : 11
                : 2
                : 138-149
                Affiliations
                Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
                Gubra ApS, Hørsholm 2970, Denmark
                Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup 2900, Denmark
                Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
                Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
                Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, the Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, China
                Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
                Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark
                Clinical Metabolic Physiology, Steno Diabetes Center Copenhagen, Gentofte Hospital, Hellerup 2900, Denmark
                Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
                Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
                Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark. henngroe@ 123456rm.dk
                Author notes

                Author contributions: All authors contributed to the conception and design of this study, literature review and analysis, drafting, critical revision and editing, and approved the final version of this manuscript.

                Corresponding author: Henning Grønbæk, MD, PhD, Professor, Department of Hepatology and Gastroenterology, Aarhus University Hospital, 99 Palle Juul-Jensens Boulevard, Entrance C, Level 1, C116, Aarhus N DK-8200, Denmark.

                Telephone: +45-21-679281

                Article
                jWJH.v11.i2.pg138
                10.4254/wjh.v11.i2.138
                6393715
                30820265
                392d4040-11ee-4935-b3df-3f1607233413
                ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                : 5 October 2018
                : 1 November 2018
                : 4 December 2018
                Categories
                Review

                non-alcoholic fatty liver disease,non-alcoholic steatohepatitis,bariatric surgery,insulin resistance, gut hormones,glucagon-like peptide 1,steatosis,inflammation,fibrosis

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