Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors - PubMed (original) (raw)

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Non-Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors

Oriol Juanola et al. Int J Environ Res Public Health. 2021.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of chronic liver disease in the Western world, probably due to the growing prevalence of obesity, metabolic diseases, and exposure to some environmental agents. In certain patients, simple hepatic steatosis can progress to non-alcoholic steatohepatitis (NASH), which can sometimes lead to liver cirrhosis and its complications including hepatocellular carcinoma. Understanding the mechanisms that cause the progression of NAFLD to NASH is crucial to be able to control the advancement of the disease. The main hypothesis considers that it is due to multiple factors that act together on genetically predisposed subjects to suffer from NAFLD including insulin resistance, nutritional factors, gut microbiota, and genetic and epigenetic factors. In this article, we will discuss the epidemiology of NAFLD, and we overview several topics that influence the development of the disease from simple steatosis to liver cirrhosis and its possible complications.

Keywords: metabolic syndrome; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; obesity; type 2 diabetes mellitus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Major risk factors and pathophysiology of NAFLD. Genetically susceptible individuals under adverse environmental conditions including smoking, air pollution, and/or poor diet enriched in fat/fructose are prone to developing NAFLD. Obesity, MS, T2DM, dyslipidemia, and age increase the risk for fatty liver disease. Increased energy uptake due to high fat diet leads to an increased body fat, peripheral tissue insulin resistance, and metabolic syndrome. Augmented lipolysis, de novo lipogenesis, and constant absorption of high-energy nutrients induce increased FFAs and ultimately hepatic steatosis. Lipotoxicity, due to increased levels of lipids in the liver, induce production of ROS due to increased lipid oxidation and ER stress. Poor diet in vulnerable patients may induce intestinal dysbiosis associated with reduced production of SCFAs and increased intestinal permeability. Bacterial translocation of bacteria or its products to the liver result in activation of immune cells, hepatocytes, and LSECs, and release of proinflammatory cytokines. Production of ROS and proinflammatory cytokines drive the activation of HSCs and deposition of collagen inducing fibrosis and progression of liver disease from simple steatosis to steatohepatitis, cirrhosis and hepatocellular carcinoma. MS: Metabolic syndrome; T2DM—Type 2 diabetes mellitus; SCFAs—Short-chain fatty acids; FFA—Free fatty acids; TG—Triglyceride; VLDL—Very low-density lipoprotein; ER—Endothelial reticulum; ROS—Reactive oxygen species; LSECs—Liver sinusoidal endothelial cells; HSC—Hepatic stellate cells; NAFLD—Non-alcoholic fatty liver disease; NASH—Non-alcoholic steatohepatitis. This figure was created using the BioRender platform.

References

    1. Sanyal A.J., Brunt E.M., Kleiner D.E., Kowdley K.V., Chalasani N., Lavine J.E., Ratziu V., McCullough A. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54:344–353. doi: 10.1002/hep.24376. - DOI - PMC - PubMed
    1. Cohen J.C., Horton J.D., Hobbs H.H. Human fatty liver disease: Old questions and new insights. Science. 2011;332:1519–1523. doi: 10.1126/science.1204265. - DOI - PMC - PubMed
    1. Perry R.J., Samuel V.T., Petersen K.F., Shulman G.I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature. 2014;510:84–91. doi: 10.1038/nature13478. - DOI - PMC - PubMed
    1. Diehl A.M., Day C. Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2017;377:2063–2072. doi: 10.1056/NEJMra1503519. - DOI - PubMed
    1. Chalasani N., Younossi Z., Lavine J.E., Charlton M., Cusi K., Rinella M., Harrison S.A., Brunt E.M., Sanyal A.J. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67:328–357. doi: 10.1002/hep.29367. - DOI - PubMed

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