A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP-2

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dc.contributor.authorLi, Y.
dc.contributor.authorSong, Y.
dc.contributor.authorZhao, M.
dc.contributor.authorGuo, Y.
dc.contributor.authorYu, C.
dc.contributor.authorChen, W.
dc.contributor.authorShao, S.
dc.contributor.authorXu, C.
dc.contributor.authorZhou, X.
dc.contributor.authorZhao, L.
dc.contributor.authorZhang, Z.
dc.contributor.authorBo, T.
dc.contributor.authorXia, Y.
dc.contributor.authorProud, C.
dc.contributor.authorWang, X.
dc.contributor.authorWang, L.
dc.contributor.authorZhao, J.
dc.contributor.authorGao, L.
dc.date.issued2017
dc.description.abstractCholesterol synthesis is regulated by the transcription factor sterol regulatory element binding protein 2 (SREBP-2) and its target gene 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), which is the rate-limiting enzyme in cholesterol synthesis. Cyclic adenosine monophosphate-responsive element (CRE) binding protein-regulated transcription coactivator (CRTC) 2 is the master regulator of glucose metabolism. However, the effect of CRTC2 on cholesterol and its potential molecular mechanism remain unclear. Here, we demonstrated that CRTC2 expression and liver cholesterol content were increased in patients with high serum cholesterol levels who underwent resection of liver hemangiomas, as well as in mice fed a 4% cholesterol diet. Mice with adenovirus-mediated CRTC2 overexpression also showed elevated lipid levels in both serum and liver tissues. Intriguingly, hepatic de novo cholesterol synthesis was markedly increased under these conditions. In contrast, CRTC2 ablation in mice fed a 4% cholesterol diet (18 weeks) showed decreased lipid levels in serum and liver tissues compared with those in littermate wild-type mice. The expression of lipogenic genes (SREBP-2 and HMGCR) was consistent with hepatic CRTC2 levels. In vivo imaging showed enhanced adenovirus-mediated HMGCR-luciferase activity in adenovirus-mediated CRTC2 mouse livers; however, the activity was attenuated after mutation of CRE or sterol regulatory element sequences in the HMGCR reporter construct. The effect of CRTC2 on HMGCR in mouse livers was alleviated upon SREBP-2 knockdown. CRTC2 modulated SREBP-2 transcription by CRE binding protein, which recognizes the half-site CRE sequence in the SREBP-2 promoter. CRTC2 reduced the nuclear protein expression of forkhead box O1 and subsequently increased SREBP-2 transcription by binding insulin response element 1, rather than insulin response element 2, in the SREBP-2 promoter.CRTC2 regulates the transcription of SREBP-2 by interfering with the recognition of insulin response element 1 in the SREBP-2 promoter by forkhead box O1, thus inducing SREBP-2/HMGCR signaling and subsequently facilitating hepatic cholesterol synthesis. (Hepatology 2017;66:481-497).
dc.description.statementofresponsibilityYujie Li, Yongfeng Song, Meng Zhao, Yanjing Guo, Chunxiao Yu, Wenbin Chen, Shanshan Shao, Chao Xu, Xinli Zhou, Lifang Zhao, Zhenhai Zhang, Tao Bo, Yu Xia, Christopher G. Proud, Xuemin Wang, Li Wang, Jiajun Zhao, Ling Gao
dc.identifier.citationHepatology, 2017; 66(2):481-497
dc.identifier.doi10.1002/hep.29206
dc.identifier.issn0270-9139
dc.identifier.issn1527-3350
dc.identifier.orcidProud, C. [0000-0003-0704-6442]
dc.identifier.urihttp://hdl.handle.net/2440/113030
dc.language.isoen
dc.publisherWiley
dc.rights© 2017 The Authors. H EPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
dc.source.urihttps://doi.org/10.1002/hep.29206
dc.subjectSterol Regulatory Element Binding Protein 2
dc.titleA novel role for CRTC2 in hepatic cholesterol synthesis through SREBP-2
dc.typeJournal article
pubs.publication-statusPublished

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