The regulation of acetyl-CoA carboxylase--a potential target for the action of hypolipidemic agents.

ACC exists as two major isoforms ACC1 or ACC alpha, and ACC2 or ACC beta, and there is evidence that they play separate roles in the production of malonyl-CoA for fatty acid synthesis and the control of mitochondrial beta-oxidation, respectively. ACC alpha can be regulated at the level of gene expression, allosteric regulation of the enzyme, and reversible phosphorylation by AMP-PK. Emerging lines of research suggest that similar mechanisms of regulation exist for ACC beta. Its inactivation in heart and skeletal muscle through phosphorylation by AMP-PK is becoming well-established. ACC is an important target of certain hypolipidemic drugs such as the fibrates. This is not simply because ACC alpha inhibition decreases the synthesis of a lipid component of VLDL because fatty acids synthesized de novo in liver are not always major contributors to VLDL lipid (158); it is also because ACC beta inhibition leads to a decrease in malonyl-CoA levels and the disinhibition of fatty acid oxidation. Partitioning fatty acids towards oxidation and away from esterification is an important aspect of the lipid-lowering effects of fibrates. Fibrates could use any of the mechanisms of ACC regulation to decrease activity. They could repress ACC gene expression through the activation of PPAR alpha, and fibroyl-CoA esters could inhibit ACC allosterically just as TOFyl-CoA does. However, we have demonstrated a rapid inactivation of ACC in cultured rat hepatocytes by gemfibrozil that is mediated by activation of AMP-PK and the subsequent phosphorylation of ACC. The end result is the inhibition of hepatic fatty acid synthesis and a possible activation of beta-oxidation as evidenced by the increased production of ketone bodies. The mechanism through which fibrates activate the AMP-PK cascade, the role of PPAR alpha, the physiological responses of biosynthesis and oxidation and the use of these mechanisms by other hypolipidemic agents are areas of ongoing investigation.