The SCAP/SREBP Pathway: A Mediator of Hepatic Steatosis

Figures

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  Fig. 1. Metabolic alterations that cause hepatic steatosis in insulin-resistant states. Fatty acids in the liver are derived from diet, de novo synthesis, and peripheral adipose tissue. In insulin-resistant states, lipases in adipocytes are not inhibited by insulin, and free fatty acids (FFAs) are released continuously and taken up by hepatocytes. In the liver, hyperinsulinemia induces sterol regulatory element binding protein-1c (SREBP-1c) activity, which increases the de novo synthesis of fatty acids. Fatty acid oxidation in mitochondria is reduced due to the inhibition of carnitine palmitoyl transferase-1 by the malonyl-coenzyme A (CoA) generated from de novo fatty acid synthesis. Therefore, free fatty acids in the liver are preferentially esterified to triglycerides (TG). ChREBP, carbohydrate response element binding protein; VLDL, very low density lipoprotein; ATGL, adipose triglyceride lipase; HSL, hormone sensitive lipase.

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  Fig. 2. Activation of sterol regulatory element binding protein (SREBP). SREBPs are synthesized as inactive precursors that exist in the endoplasmic reticulum (ER) membrane. SREBP cleavage activating protein (SCAP) escorts SREBPs from the ER to the Golgi where two proteases release the NH2-teminal region of SREBPs. The NH2-teminal region of SREBPs moves to the nucleus and activates transcription of the target genes. INSIG, insulin induced gene; bHLH, basic helix-loop-helix.