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.

Fig. 1

Mechanisms of hepatocellular lipid metabolism and their dysregulation in non-alcoholic fatty liver disease (NAFLD). Fatty acid uptake: fatty acid transport protein (FATP) 2, FATP5 and CD36 mediate transport of non-esterified fatty acids (NEFA) across the plasma membrane. Once taken up into cytosol, fatty acids are activated to form acyl-CoAs by the activity of FATPs or fatty acyl-CoA synthetases (ACSs). De novo lipogenesis: palmitic acid is newly synthesized from glucose. Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) catalyze the rate-limiting and final steps, respectively. After ACS-mediated activation, palmitoyl-CoA is elongated by long chain fatty acid elongase 6 (ELOVL6) and desaturated by stearoyl-CoA desaturase 1 (SCD1). Acyl-CoAs are esterified by glycerol-3-phosphate (G-3-P) acyltransferase (GPAT) to form lysophosphatidic acid (LPA) and by 1-acylglycerol-3-phosphate acyltransferase (AGPAT) to form phosphatidic acid (PA). PA is dephosphorylated by lipin 1 to form diacylglycerol (DAG), which is esterified to another acyl-CoA molecule to form triglyceride (TG) by acyl-CoA:diacylglycerol acyltransferase (DGAT). Fatty acid oxidation: acyl-CoAs are transported into mitochondria across the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM) by the activities of carnitine palmitoyl transferase (CPT) 1, CPT2 and carnitine acylcarnitine translocase (CACT). Within mitochondria, acyl-CoAs are oxidized to form acetyl-CoA. Very low density lipoprotein (VLDL) synthesis: TGs are packaged together with apoB 100 into VLDL in the endoplasmic reticulum (ER) by the activity of microsomal triglyceride transfer protein (MTP) and secreted into space of Disse. Pink arrows denote the increases and decreases that occur in NAFLD and are described in the text. In NAFLD patients, enhanced acquisition of fatty acids through uptake and rates of de novo lipogenesis are not compensated by possible increases in rates of fatty acid oxidation or higher production rates of VLDL particles