title: A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP-2.
abstract: Cholesterol 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).
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Yanjing
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Shao
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Institute of Hepatobiliary Surgery, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
authors.forename: Zhenhai
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.
authors.forename: Tao
authors.identifier: 0000-0001-9083-4639
authors.initials: T
authors.lastname: Bo
authors.affiliation: Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.affiliation: South Australian Health and Medical Research Institute, North Terrace, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Proud
authors.affiliation: South Australian Health and Medical Research Institute, North Terrace, Australia.|School of Biological Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Physiology and Neurobiology and The Institute for Systems Genomics, University of Connecticut, Storrs, CT.|Veterans Affairs Connecticut Healthcare System, West Haven, CT.|School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.|Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Shandong, China.|Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Shandong, China.|Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D002791:Cholesterol, Dietary / Q000009:adverse effects; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D050155:Lipogenesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D012494:Sampling Studies; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D002791:Cholesterol, Dietary; C504923:Crtc2 protein, mouse; D012333:RNA, Messenger; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D002784:Cholesterol