Fatty acid metabolism: target for metabolic syndrome

Abstract

Fatty acids are a major energy source and important constituents of membrane lipids, and they serve as cellular signaling molecules that play an important role in the etiology of the metabolic syndrome. Acetyl-CoA carboxylases 1 and 2 (ACC1 and ACC2) catalyze the synthesis of malonyl-CoA, the substrate for fatty acid synthesis and the regulator of fatty acid oxidation. They are highly regulated and play important roles in the energy metabolism of fatty acids in animals, including humans. They are presently considered as an attractive target to regulate the human diseases of obesity, diabetes, cancer, and cardiovascular complications. In this review we discuss the role of fatty acid metabolism and its key players, ACC1 and ACC2, in animal evolution and physiology, as related to health and disease.

Fig. 1.

Acetyl-coenzyme A carboxylase 1 (ACC1) and acetyl-coenzyme A carboxylase 2 (ACC2) play distinct roles in lipid metabolism in animal tissues. Diet fat, carbohydrate, and protein are digested, and the fatty acids (FA), glucose, and amino acids are transported to various tissues, including liver, adipose, and muscle. In liver, FA are converted to acyl-CoA; glucose undergoes glycolysis and generates pyruvate, which is oxidized in the mitochondria through pyruvate dehydrogenase to acetyl-coenzyme A (acetyl-CoA). Acetyl-CoA is also produced through amino acid metabolism. The acyl-CoA are shuttled into the mitochondria through carnitine/palmitoyl-transferase 1 (CPT1) for β-oxidation and generation of acetyl-CoA. Acetyl-CoA is oxidized through the citric acid cycle to yield energy, H₂O, and CO₂ or it is converted to (1) citrate, which exits to the cytosol and generates acetyl-CoA through ATP citrate lyase (ACLY), or to (2) ketone bodies, through the hydroxymethylglutaryl-CoA (HMG-CoA) system, or to (3) carnitine/acetyl-CoA (CAT), which exits from the mitochondria to the cytosol. In the cytosol acetyl-CoA is carboxylated to malonyl-CoA by ACC1 and utilized through fatty acid synthase (FAS) reactions to generate palmitate, which is utilized in the synthesis of triglycerides (TG) and VLDL. Also, acetyl-CoA is carboxylated by ACC2 at the mitochondrial membrane to form malonyl-CoA, which inhibits the CPT1 and reduces acyl-CoA transfer to mitochondria for β-oxidation. Basically comparable reactions, with appropriate modifications, occur in adipose and muscle tissues. See the text for a discussion of the impact of ACC2 knockout on fatty acid metabolism.

Fig. 2.

Lack of ACC2 improves insulin signaling in animal tissues. Obese tissues lead to insulin resistance. High acyl-CoA activates PKC Ø, resulting in a cascade of serine and threonine kinases and increasing serine and threonine phosphorylation of insulin receptor substrates, IRS-1 and IRS-2. These substrates generate IRS-Ser-p Thr-p, which decreases the activity of PI 3 kinase, down-regulates AKT, and decreases the translocation of GLUT4 to the plasma membrane, leading to a decrease in glucose uptake (black arrows). As a result of ACC2 deletion (red X), tissues continuously oxidize FA in the mitochondria; this leads to a decrease of FA levels, the down-regulation of PKC Ø, a decrease in the Ser-p Thr-p of IRS1 and IRS2, an increase in IRS-Tyr-p, and the up-regulation of insulin signaling, thereby increasing glucose uptake and lowering the plasma blood glucose level.