Molecular mediators of hepatic steatosis and liver injury
J. Clin. Invest. Jeffrey D. Browning, et al. 114:147 doi:10.1172/JCI22422 [Go to this article.]

Figure 1
Metabolic alterations resulting in hepatic triglyceride accumulation in insulin-resistant states. Insulin resistance is manifested by hyperinsulinemia, increased hepatic glucose production, and decreased glucose disposal. In adipocytes, insulin resistance increases hormone-sensitive lipase (HSL) activity, resulting in elevated rates of triglyceride lipolysis and enhanced FFA flux to the liver. FFAs can either be oxidized in the mitochondria to form ATP or esterified to produce triglycerides for storage or incorporation into VLDL particles. In liver, hyperinsulinemia induces SREBP-1c expression, leading to the transcriptional activation of all lipogenic genes. Simultaneously, hyperglycemia activates ChREBP, which transcriptionally activates L-PK and all lipogenic genes. The synergistic actions of SREBP-1c and ChREBP coordinately activate the enzymatic machinery necessary for the conversion of excess glucose to fatty acids. A consequence of increased fatty acid synthesis is increased production of malonyl-CoA, which inhibits CPT-1, the protein responsible for fatty acid transport into the mitochondria. Thus, in the setting of insulin resistance, FFAs entering the liver from the periphery, as well as those derived from de novo lipogenesis, will be preferentially esterified to triglycerides. ACL, ATP citrate lyase; CPT-1, carnitine palmitoyl transferase-1; FAS, fatty acid synthase; LCE, long-chain fatty acyl elongase.