A putative role of micro RNA in regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes.
Cholesterol 7alpha-hydroxylase (CYP7A1) plays a critical role in regulation of bile acid synthesis in the liver. CYP7A1 mRNAs have very short half-lives, and bile acids destabilize CYP7A1 mRNA via the 3'-untranslated region (3'-UTR). However, the underlying mechanism of translational regulation of CYP7A1 mRNA remains unknown. Screening of a human micro RNA (miRNA) microarray has identified five differentially expressed miRNAs in human primary hepatocytes treated with chenodeoxycholic acid, GW4064, or fibroblast growth factor (FGF)19. These compounds also significantly induced the expression of miR-122a, a liver-specific and the predominant miRNA in human hepatocytes. The putative recognition sequences for miR-122a and miR-422a were localized in the 3'-UTR of human CYP7A1 mRNA. The miR-122a and miR-422a mimics inhibited, whereas their inhibitors stimulated CYP7A1 mRNA expression. These miRNAs specifically inhibited the activity of the CYP7A1-3'-UTR reporter plasmids, and mutations of miRNA binding sites in 3'-UTR abrogated miRNA inhibition of reporter activity. These results suggest that miR-122a and miR-422a may destabilize CYP7A1 mRNA to inhibit CYP7A1 expression. However, these miRNAs did not play a role in mediating FGF19 inhibition of CYP7A1 transcription. Under certain conditions, miRNA may reduce CYP7A1 mRNA stability to inhibit bile acid synthesis, and the miR-122a antagomirs may stimulate bile acid synthesis to reduce serum cholesterol and triglycerides.
Song
Kwang-Hoon
KH
Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA.
Li
Tiangang
T
Owsley
Erika
E
Chiang
John Y L
JY
D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D020413:3' Untranslated Regions; C117476:FGF19 protein, human; D007555:Isoxazoles; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D002635:Chenodeoxycholic Acid; D005346:Fibroblast Growth Factors; D002790:Cholesterol 7-alpha-Hydroxylase; C412815:GW 4064