Effect of iron on cholesterol 7α-hydroxylase expression in alcohol-induced hepatic steatosis in mice

• Published in: Journal of lipid research Vol. 58; no. 8; pp. 1548 - 1560
• Main Authors: Liang, Huan, Huang, Hui, Tan, Pei-zhu, Liu, Ying, Nie, Jun-hui, Zhang, Yi-tong, Zhang, Kai-li, Diao, Yan, He, Qi, Hou, Bao-yu, Zhao, Ting-ting, Li, Yan-ze, Lv, Gui-xiang, Lee, Ki-Young, Gao, Xu, Zhou, Ling-yun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2017; Journal of Lipid Research; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: 3' Untranslated regions; 3' Untranslated Regions - genetics; alcoholic fatty liver disease; Animals; Base Sequence; Cell Line; Cholesterol; Cholesterol 7-alpha-Hydroxylase - genetics; Ethanol - adverse effects; Fatty liver; Fatty Liver, Alcoholic - genetics; Fatty Liver, Alcoholic - metabolism; Gene Expression Regulation, Enzymologic - drug effects; Homeostasis; Hydroxylase; Iron; Iron - pharmacology; iron regulatory protein 1; iron regulatory protein 2; Lipid metabolism; Lipids; Liver diseases; Metabolism; Mice; Mice, Inbred C57BL; mouse models; non-canonical IRE; Regulatory proteins; Response Elements - genetics; RNA Stability; Steatosis; Transcription; transcriptional regulation; mouse models; iron regulatory protein 2; non-canonical IRE; alcoholic fatty liver disease; iron regulatory protein 1; transcriptional regulation
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M074534

Both iron and lipids are involved in the progression of alcoholic fatty liver disease (AFLD), but the interaction between iron and lipids in AFLD is unclear. Here, we tested the hypothesis that iron regulates the expression of genes involved in lipid metabolism through iron regulatory proteins (IRPs), which interact with the iron-responsive elements (IREs) in the untranslated regions (UTRs) of genes, resulting in lipid accumulation. Using “RNA structure software”, we predicted the mRNA secondary structures of more than 100 genes involved in lipid metabolism to investigate whether the IRE structure exists in novel mRNAs. Cholesterol 7α-hydroxylase (Cyp7a1) has an IRE-like stem-loop, a noncanonical IRE structure, in its 3′-UTR. Cyp7a1 expression can be regulated by in vivo and in vitro iron treatment. In addition, the noncanonical IRE motif can efficiently bind both to IRP1 and IRP2. The results indicate that hepatic iron overloading in AFLD mice decreased Cyp7a1 expression and resulted in cholesterol accumulation, providing a new mechanism of iron-regulated gene transcription and translation through the interaction between iron and a noncanonical IRE structure in Cyp7a1 mRNA. This finding has significant implications in studying a proposed mechanism for the regulation of cholesterol homeostasis by an Fe/IRP/noncanonical IRE axis.