Fatty acid synthase and liver triglyceride metabolism: housekeeper or messenger?

Abstract

Fatty acid synthase (FAS) catalyzes the de novo synthesis of fatty acids. In the liver, FAS has long been categorized as a housekeeping protein, producing fat for storage of energy when nutrients are present in excess. Most previous studies of FAS regulation have focused on the control of gene expression. However, recent findings suggest that hepatic FAS may also be involved in signaling processes that include activation of peroxisome proliferator-activated receptor α (PPARα). Moreover, reports of rapid alterations in FAS activity as well as findings of post-translational modifications of the FAS protein support the notion that dynamic events in addition to transcription impact FAS regulation. These results indicate that FAS enzyme activity can impact liver physiology through signaling as well as energy storage and that its regulation may be complex. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

Figure 1. The role of FAS in hepatic triglyceride metabolism

Fatty acid synthase controls fatty acid catabolism through the synthesis of a ligand for PPARα, which activates fatty acid oxidation genes. FAS makes a minor contribution of lipids to stored and secreted triglycerides, with the major contributions coming from plasma free fatty acids and dietary fats from chylomicron remnants. 16:0/18:1 GPC, 16:0/18:1-glycerophosphocholine; DAG, diacylglycerol; FAS, fatty acid synthase; FFA, free fatty acid; PPARα, peroxisome proliferator-activated receptor alpha; RXR, retinoid X receptor; TAG, triacylglycerol (triglyceride); VLDL, very low-density lipoprotein.

Figure 2. The mouse proximal FAS promoter

Regulatory elements and nuclear factor binding site nucleotides are highlighted in yellow. IRE, insulin response element; LXRE, liver X receptor element; Nf-Y, nuclear factor Y binding site; Sp1, specificity factor 1 binding site; SRE, sterol regulatory element.