Forkhead box transcription factor O1 inhibits cholesterol 7alpha-hydroxylase in human hepatocytes and in high fat diet-fed mice.
The conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism. Bile acids are metabolic regulators of triglycerides and glucose metabolism in the liver. This study investigated the roles of FoxO1 in the regulation of cholesterol 7alpha-hydroxylase (CYP7A1) gene expression in primary human hepatocytes. Adenovirus-mediated expression of a phosphorylation defective and constitutively active form of FoxO1 (FoxO1-ADA) inhibited CYP7A1 mRNA expression and bile acid synthesis, while siRNA knockdown of FoxO1 resulted in a approximately 6-fold induction of CYP7A1 mRNA in human hepatocytes. Insulin caused rapid exclusion of FoxO1 from the nucleus and resulted in the induction of CYP7A1 mRNA expression, which was blocked by FoxO1-ADA. In high fat diet-fed mice, CYP7A1 mRNA expression was repressed and inversely correlated to increase hepatic FoxO1 mRNA expression and FoxO1 nuclear retention. In conclusion, our current study provides direct evidence that FoxO1 is a strong repressor of CYP7A1 gene expression and bile acid synthesis. Impaired regulation of FoxO1 may cause down-regulation of CYP7A1 gene expression and contribute to dyslipidemia in insulin resistance.
Li
Tiangang
T
Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, 4209 State Route 44, Rootstown, OH 44272, USA.
Ma
Huiyan
H
Park
Young Joo
YJ
Lee
Yoon-Kwang
YK
Strom
Stephen
S
Moore
David D
DD
Chiang
John Y L
JY
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage* / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034622:RNA Interference / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D001647:Bile Acids and Salts; D004041:Dietary Fats; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D012333:RNA, Messenger; D002790:Cholesterol 7-alpha-Hydroxylase