Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease

Abstract

Nonalcoholic 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.

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

“…ESM Table 3 displays the overall significance of the clusters reached for the two knockout models as compared with wild-type mice. Five metabolite clusters displayed high significance for both knockout models (clusters 4,8,10,13,15), consisting of phospholipids, triacylglycerols, AAA and BCAA, as well as glycine, histidine and trans-4-hydroxyproline. Interestingly, four clusters (clusters 1, 5, 9, 11)-mainly consisting of amino acids, hexoses and catabolites-showed overall significant changes only between db/db and C57BLKS/J wild-type mice.…”

A short bout of HFD promotes long-lasting hepatic lipid accumulation

“…Besides FFA uptake, liver lipid accumulation is influenced by de novo lipogenesis and b-oxidation. 12 Therefore, hepatic mRNA expression of enzymes involved in these pathways was determined. While expression of lipogenic enzymes was similar between both groups, mRNA expression of the b-oxidation genes Acox1, Cpt1 and Ppara was increased in livers of HFD RF mice (Fig.…”

Metabolomic‐based noninvasive serum test to diagnose nonalcoholic steatohepatitis: Results from discovery and validation cohorts

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