Fig. 1.

Overview of lipid metabolism. Lipid metabolism consists of two distinct arms, namely, fatty acid oxidation (β-oxidation) and lipid synthesis. The peroxisome proliferator-activated receptor (PPAR) family of transcription factors regulates the expression of genes involved in β-oxidation, as depicted in blue. However, the sterol regulatory element binding protein (SREBP) family of transcription factors controls the expression of enzymes and transport proteins required for fatty acid and cholesterol synthesis, as shown in red. Briefly, cytosolic fatty acids (FAs) are activated by fatty acyl-CoA synthetase (FACS), which introduces a CoA adduct, yielding fatty acyl-CoA. Long-chain fatty acyls enter the mitochondria for oxidation via the carnitine shuttle system. Carnitine palmitoyl-transferase 1 (Cpt1), located on the outer mitochondrial membrane, exchanges the CoA adduct for a carnitine molecule, forming acylcarnitine. Acylcarnitines are transported into the mitochondrial matrix through carnitine acyl-carnitine translocase (CACT), where they are reconverted back to fatty acyl-CoA by the action of Cpt2. Once inside the matrix, fatty acyl-CoA undergoes a series of dehydration, hydration and thiolysis reactions (β-oxidation), which generate NADH and FADH₂ reducing equivalents and acetyl-CoA. NADH and FADH₂ donate electrons to complexes 1 and 2 of the electron transport chain and acetyl-CoA enters the tricarboxylic acid (TCA) cycle. In the TCA cycle, acetyl-CoA is converted into citrate, which may be exported to the cytosol through Slc25a1. The enzyme ATP citrate lyase (ACLY) catalyses the conversion of cytosolic citrate to acetyl-CoA, which is an important step in endogenous lipid synthesis. Cytosolic acetyl-CoA is converted to malonyl-CoA through the action of acetyl-CoA carboxylase (ACC), which together form the major substrates for fatty acid synthesis by the multienzyme complex fatty acid synthase (FASN). FASN catalyzes the synthesis of palmitic acid, a 16 carbon saturated fatty acid, which may be converted into palmitoleic acid, a 16-carbon unsaturated fatty acid through the action of stearoyl-CoA desaturase (SCD). In addition, cytosolic acetyl-CoA may enter the mevalonate pathway, resulting in the production of cholesterol and other steroids. Together, fatty acids and cholesterol play an important role in membrane synthesis and signaling and can also be stored in lipid droplets to be later used as a fuel source