Hormonal Regulation of Acetyl-CoA Carboxylase Isoenzyme Gene Transcription

Abstract

Both glucocorticoid and insulin are known to have an anabolic effect on lipogenesis. Acetyl-CoA, an intermediate product of glycolysis, is supplied for fatty acid synthesis when carbohydrate intake is sufficient. Acetyl-CoA carboxylase (ACC), consisting of two isoenzymes ACC1 and ACC2, mediates the conversion from acetyl-CoA to malonyl-CoA, and thus plays a key role for the regulation of lipogenesis. In this study, we surveyed the effects of glucocorticoid and insulin on the transcriptional activity of the alternative promoters of ACCs (PI-PIII for ACC1, and PI and PII for ACC2) using the HepG2 human hepatocyte cell line in vitro. We also examined the roles of the insulin and/or glucose-regulated transcriptional factor(s) such as SREBP1c, LXRα/β, and ChREBP on each promoter of the ACC genes. We found that both insulin and glucocorticoid had potent positive effects on all the promoters examined, and additive effects of both hormones were recognized in ACC1 PI and ACC2 PI. Furthermore, a representative insulin-responsive transcription factor SREBP1c showed significant stimulatory effects on all the promoters of ACC genes, among which those on ACC1 PIII and ACC2 PI were most prominent. On the other hand, the effect of LXRα was rather selective; it showed a marked stimulatory effect only on ACC1 PII. LXRβ and ChREBP had minimal, if any, effects on some of the promoters. Altogether, our data suggest that insulin and glucocorticoid have positive effects on both ACC1 and ACC2 gene transcription. SREBP1c might be a master regulator of the expression of both genes regardless of the promoter utilized, whereas LXRα seems to play a promoter-specific role. Since ACC1 facilitates lipogenesis by stimulating fatty acid synthesis and ACC2 inhibits lipolysis, both insulin and glucocorticoid seem to play an important role in the pathogenesis of obesity and/or hepatic steatosis.