Abstract 12223: Regulation of Acat2 Expression by Hnf4 and its Cofactors Pgc1α and Shp
ACAT2, one member of ACAT family catalyzing formation of cholesterol esters, is important for cholesterol ester synthesis and VLDL/ApoB secretion. To explore how ACAT2 quantity is regulated, we studied the mechanism for controlling ACAT2 expression at transcriptional level. We found that HNF4, one liver enriched transcription factor, positively regulated ACAT2 expression. In luciferase reporter assay, HNF4 overexpression stimulated ACAT2 promoter activity. However, mutation of two response elements of HNF4 profoundly antagonized HNF4 effect. Moreover, HNF4 binds to these two elements in the promoter of ACAT2 as evidenced by EMSA and ChIP assays, In HuH7 cells, overexpression of HNF4 increased ACAT2 mRNA levels, whereas knockdown of HNF4 inhibited ACAT2 mRNA expression. ACAT2 expression was also upregulated by PGC1α, coactivator of HNF4, but decreased by SHP, corepsressor of HNF4. SHP competed with PGC1α to regulate ACAT2 promoter activity in luciferase reporter assay. Moreover, ACAT2 expression was regulated by bile acid which was reported to increase SHP level. In hepatic cells, treatment of CDCA and LCA, but not CA, inhibited ACAT2 expression. In rat, bile duct ligation caused an increase of total bile acid content and a concomitant decrease of ACAT2 expression. Thus, our results indicate that ACAT2 expression is regulated by a complex system composed of HNF4, PGC1α and SHP, providing new insights into the mechanism for regulating cholesterol ester and VLDL metabolism by transcription (co)factors.
- © 2011 by American Heart Association, Inc.