PMID:20139635

Citation	Zhao, LF, Iwasaki, Y, Zhe, W, Nishiyama, M, Taguchi, T, Tsugita, M, Kambayashi, M, Hashimoto, K and Terada, Y (2010) Hormonal regulation of acetyl-CoA carboxylase isoenzyme gene transcription. Endocr. J. 57:317-24
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, LXRalpha/beta, 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 LXRalpha was rather selective; it showed a marked stimulatory effect only on ACC1 PII. LXRbeta 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 LXRalpha 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.
Links	PubMed
Keywords	Acetyl-CoA Carboxylase/genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/physiology; Gene Expression; Gene Expression Regulation, Enzymologic/drug effects; Gene Expression Regulation, Enzymologic/physiology; Glucocorticoids/pharmacology; Hep G2 Cells; Hepatocytes/enzymology; Humans; Insulin/pharmacology; Isoenzymes/genetics; Kinetics; Orphan Nuclear Receptors/genetics; Orphan Nuclear Receptors/physiology; Promoter Regions, Genetic/genetics; RNA, Messenger/analysis; Reverse Transcriptase Polymerase Chain Reaction; Sterol Regulatory Element Binding Protein 1/genetics; Sterol Regulatory Element Binding Protein 1/physiology; Transcription, Genetic/drug effects; Transfection
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:ACACA	incorrect (CACAO)	GO:0046890 : regulation of lipid biosynthetic process	ECO:0000304:		P		intro ...... ACC1 plays a crucial role in the regulation of lipogenesis	complete
MOUSE:ACACA	incorrect (CACAO)	GO:0055088: lipid homeostasis	ECO:0000304:		P		intro Liver specific ACC1 knockout mice show decreased hepatic triglyceride accumulation	complete
HUMAN:ACACA		GO:0071548 : response to dexamethasone stimulus	ECO:0000315:		P		Fig.3	complete
HUMAN:ACACA		GO:0032868 : response to insulin stimulus	ECO:0000315:		P		Fig.4	complete
MOUSE:Q9ESZ3	incorrect (CACAO)	GO:0046320: regulation of fatty acid oxidation	ECO:0000304:		P		intro ACC2 knockout mice represent enhanced β-oxidation, and thus this implies that ACC2 is critical for the regulation of lipolysis	complete
MOUSE:Q9ESZ3	incorrect (CACAO)	GO:0050994 : regulation of lipid catabolic process	ECO:0000304:		P		intro ACC2 knockout mice represent enhanced β-oxidation, and thus this implies that ACC2 is critical for the regulation of lipolysis	complete
HUMAN:ACACB		GO:0071548 : response to dexamethasone stimulus	ECO:0000315:		P		Fig.3	complete
HUMAN:ACACB		GO:0032868 : response to insulin stimulus	ECO:0000315:		P		Fig.2b	complete
HUMAN:SRBP1		GO:0045941: positive regulation of transcription	ECO:0000270:		P		Fig.5A	complete

References

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