title: Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease.
abstract: Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation in the absence of excess alcohol intake. NAFLD is the most common chronic liver disease, and ongoing research efforts are focused on understanding the underlying pathobiology of hepatic steatosis with the anticipation that these efforts will identify novel therapeutic targets. Under physiological conditions, the low steady-state triglyceride concentrations in the liver are attributable to a precise balance between acquisition by uptake of non-esterified fatty acids from the plasma and by de novo lipogenesis, versus triglyceride disposal by fatty acid oxidation and by the secretion of triglyceride-rich lipoproteins. In NAFLD patients, insulin resistance leads to hepatic steatosis by multiple mechanisms. Greater uptake rates of plasma non-esterified fatty acids are attributable to increased release from an expanded mass of adipose tissue as a consequence of diminished insulin responsiveness. Hyperinsulinemia promotes the transcriptional upregulation of genes that promote de novo lipogenesis in the liver. Increased hepatic lipid accumulation is not offset by fatty acid oxidation or by increased secretion rates of triglyceride-rich lipoproteins. This review discusses the molecular mechanisms by which hepatic triglyceride homeostasis is achieved under normal conditions, as well as the metabolic alterations that occur in the setting of insulin resistance and contribute to the pathogenesis of NAFLD.
authors: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors: Yuki
authors: Y
authors: Kawano
authors: David E
authors: DE
authors: Cohen
mesh_terms: D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D050155:Lipogenesis / Q000502:physiology; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D008079:Lipoproteins, VLDL; D014280:Triglycerides
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