ATF6α stimulates cholesterogenic gene expression and de novo cholesterol synthesis.
The activating transcription factor 6α (ATF6α) is a sensor of the endoplasmic reticulum stress response that regulates the expression of genes involved in the unfolded protein response. Here we found that forced expression of a constitutively active form of ATF6α, ATF6(N), stimulated the expression of cholesterogenic genes, including 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase, HMG-CoA synthase, and squalene synthase, and de novo cholesterol synthesis in hepatoma Huh-7 cells. An ATF6α mutant lacking the DNA-binding domain ATF6(N)ΔbZip failed to show these effects. Luciferase assays indicated that ATF6(N) overexpression stimulated the promoter activities of HMG-CoA reductase, HMG-CoA synthase, and squalene synthase. Chromatin immunoprecipitation assays revealed that ATF6(N) interacted with the promoter region of the HMG-CoA synthase gene. Collectively, these results indicate that ATF6α can regulate de novo cholesterol synthesis through stimulation of cholesterogenic gene expression.
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo.
Ryuto
R
Maruyama
Yuki
Y
Kamoshida
Makoto
M
Shimizu
Jun
J
Inoue
Ryuichiro
R
Sato
D051702:Activating Transcription Factor 6 / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis* / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D059865:Endoplasmic Reticulum Stress; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D012333:RNA, Messenger; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D006904:Hydroxymethylglutaryl-CoA Synthase; D013186:Farnesyl-Diphosphate Farnesyltransferase