A Putative Role of Micro RNA in Regulation of Cholesterol 7alpha-hydroxylase Expression in Human Hepatocytes

Overview

Journal J Lipid Res

Publisher Elsevier

Specialty Biochemistry

Date 2010 Mar 31

PMID 20351063

Citations 37

Authors

Kwang-Hoon Song

Tiangang Li

Erika Owsley

John Y L Chiang

Affiliations

Soon will be listed here.

Abstract

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.

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References

Pandak W, Stravitz R, Lucas V, Heuman D, Chiang J . Hep G2 cells: a model for studies on regulation of human cholesterol 7alpha-hydroxylase at the molecular level. Am J Physiol. 1996; 270(3 Pt 1):G401-10. DOI: 10.1152/ajpgi.1996.270.3.G401. View

Krutzfeldt J, Rajewsky N, Braich R, Rajeev K, Tuschl T, Manoharan M . Silencing of microRNAs in vivo with 'antagomirs'. Nature. 2005; 438(7068):685-9. DOI: 10.1038/nature04303. View

Lewis B, Burge C, Bartel D . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005; 120(1):15-20. DOI: 10.1016/j.cell.2004.12.035. View

Esau C, Davis S, Murray S, Yu X, Pandey S, Pear M . miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006; 3(2):87-98. DOI: 10.1016/j.cmet.2006.01.005. View

Noshiro M, Nishimoto M, Okuda K . Rat liver cholesterol 7 alpha-hydroxylase. Pretranslational regulation for circadian rhythm. J Biol Chem. 1990; 265(17):10036-41. View

Agellon L, Cheema S . The 3'-untranslated region of the mouse cholesterol 7alpha-hydroxylase mRNA contains elements responsive to post-transcriptional regulation by bile acids. Biochem J. 1998; 328 ( Pt 2):393-9. PMC: 1218933. DOI: 10.1042/bj3280393. View

Enright A, John B, Gaul U, Tuschl T, Sander C, Marks D . MicroRNA targets in Drosophila. Genome Biol. 2004; 5(1):R1. PMC: 395733. DOI: 10.1186/gb-2003-5-1-r1. View

Xie Y, Blanc V, Kerr T, Kennedy S, Luo J, Newberry E . Decreased expression of cholesterol 7alpha-hydroxylase and altered bile acid metabolism in Apobec-1-/- mice lead to increased gallstone susceptibility. J Biol Chem. 2009; 284(25):16860-16871. PMC: 2719322. DOI: 10.1074/jbc.M109.010173. View

Song K, Ellis E, Strom S, Chiang J . Hepatocyte growth factor signaling pathway inhibits cholesterol 7alpha-hydroxylase and bile acid synthesis in human hepatocytes. Hepatology. 2007; 46(6):1993-2002. DOI: 10.1002/hep.21878. View

10.

Lee Y, Schmidt D, Cummins C, Choi M, Peng L, Zhang Y . Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis. Mol Endocrinol. 2008; 22(6):1345-56. PMC: 2409274. DOI: 10.1210/me.2007-0565. View

11.

Kim I, Ahn S, Inagaki T, Choi M, Ito S, Guo G . Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res. 2007; 48(12):2664-72. DOI: 10.1194/jlr.M700330-JLR200. View

12.

Elmen J, Lindow M, Silahtaroglu A, Bak M, Christensen M, Lind-Thomsen A . Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver. Nucleic Acids Res. 2007; 36(4):1153-62. PMC: 2275095. DOI: 10.1093/nar/gkm1113. View

13.

Chiang J . Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev. 2002; 23(4):443-63. DOI: 10.1210/er.2000-0035. View

14.

Jopling C, Yi M, Lancaster A, Lemon S, Sarnow P . Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science. 2005; 309(5740):1577-81. DOI: 10.1126/science.1113329. View

15.

Inagaki T, Choi M, Moschetta A, Peng L, Cummins C, McDonald J . Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2005; 2(4):217-25. DOI: 10.1016/j.cmet.2005.09.001. View

16.

Miska E . How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev. 2005; 15(5):563-8. DOI: 10.1016/j.gde.2005.08.005. View

17.

Griffiths-Jones S, Saini H, van Dongen S, Enright A . miRBase: tools for microRNA genomics. Nucleic Acids Res. 2007; 36(Database issue):D154-8. PMC: 2238936. DOI: 10.1093/nar/gkm952. View

18.

Cheung O, Puri P, Eicken C, Contos M, Mirshahi F, Maher J . Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatology. 2008; 48(6):1810-20. PMC: 2717729. DOI: 10.1002/hep.22569. View

19.

Lundasen T, Galman C, Angelin B, Rudling M . Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man. J Intern Med. 2006; 260(6):530-6. DOI: 10.1111/j.1365-2796.2006.01731.x. View

20.

Li Y, Wang D, Chiang J . Regulation of cholesterol 7 alpha-hydroxylase in the liver. Cloning, sequencing, and regulation of cholesterol 7 alpha-hydroxylase mRNA. J Biol Chem. 1990; 265(20):12012-9. View