Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes.
Bile acids play important roles in the regulation of lipid, glucose, and energy homeostasis. Recent studies suggest that glucose regulates gene transcription in the liver. The aim of this study was to investigate the potential role of glucose in regulation of bile acid synthesis in human hepatocytes. High glucose stimulated bile acid synthesis and induced mRNA expression of cholesterol 7alpha-hydroxylase (CYP7A1), the key regulatory gene in bile acid synthesis. Activation of an AMP-activated protein kinase (AMPK) decreased CYP7A1 mRNA, hepatocyte nuclear factor 4alpha (HNF4alpha) protein, and binding to CYP7A1 chromatin. Glucose increased ATP levels to inhibit AMPK and induce HNF4alpha to stimulate CYP7A1 gene transcription. Furthermore, glucose increased histone acetylation and decreased H3K9 di- and tri-methylation in the CYP7A1 chromatin. Knockdown of ATP-citrate lyase, which converts citrate to acetyl-CoA, decreased histone acetylation and attenuated glucose induction of CYP7A1 mRNA expression. These results suggest that glucose signaling also induces CYP7A1 gene transcription by epigenetic regulation of the histone acetylation status. This study uncovers a novel link between hepatic glucose metabolism and bile acid synthesis. Glucose induction of bile acid synthesis may have an important implication in metabolic control of glucose, lipid, and energy homeostasis under normal and diabetic conditions.
Li
Tiangang
T
Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA.
Chanda
Dipanjan
D
Zhang
Yanqiao
Y
Choi
Hueng-Sik
HS
Chiang
John Y L
JY
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D001647:Bile Acids and Salts / Q000378:metabolism; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D005947:Glucose / Q000008:administration & dosage*; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000378:metabolism*; D008745:Methylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; D012333:RNA, Messenger; D002790:Cholesterol 7-alpha-Hydroxylase; D001275:ATP Citrate (pro-S)-Lyase; D055372:AMP-Activated Protein Kinases; D005947:Glucose