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. Conclusion: 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).

Estrogen Abolishes the Repression Role of gga-miR-221-5p Targeting ELOVL6 and SQLE to Promote Lipid Synthesis in Chicken Liver

“…To date, this is the first evidence of the biological function of gga-miR-221-5p controlling the lipid metabolism in the liver of egg-laying chicken. In addition, human lipid metabolism diseases are affected by many factors including lncRNA [58], miRNA [59], transcription factors [60], leucine deficiency [61], etc., and this has always been a hot topic in human research. The literature showed that gga-miR-33 can participate in lipid metabolism by targeting fat mass and obesity-associated (FTO) genes associated with obesity in chicken liver [1], and miR-33 can regulate cholesterol and fatty acid metabolism in mammals (humans and mice), which corresponds to the function of the host gene sterol regulatory element binding transcription factor 2 (SREBP2), which can regulate the synthesis and uptake of triglycerides and cholesterol [62,63], it can be seen that miR-33 functions similarly in chickens and mammals (humans and mice).…”

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

“…Seven-week-old female wildtype mice and Fshr knockout mice (estrogen-supplemented) were fed with a normal-cholesterol diet (NC) or high-cholesterol diet (HC) (4% cholesterol diet) for 20 weeks. The mice were sacrificed after fasting for approximately 8 h. 68 Ldlr knockout mice. Nine-week-old ldlr-/-mice were shamoperated (Sham) or ovariectomized (OVX).…”

“…Quantitative real-time PCR (qRT-PCR) analysis was performed in duplicate using LC480 (Roche, Mannheim, Germany) according to the instructions as previously described. 68 Western blotting Equal amounts of protein from different samples were separated in a 10% SDS-PAGE gel, then the samples were transferred from the gel to polyvinylidene difluoride membranes (Millipore). Following incubation for 1 h with 5% non-fat milk in TBST, the membranes were incubated overnight at 4°C with anti-FSHR (1:1000, Abcam, and Proteintech), anti-HMGCR (1:1000, Abcam), anti-LDLR (1:200, Abcam), anti-CYP7A1 (1:200, Abcam), anti-ABCA1 (1:200, Abcam), anti-SRB1 (1:8000, Novus), anti-ACAT2 (1:1000, Proteintech), anti-p-CREB (1:1000, CST), anti-SREBP-2 (1:1000, designed by ChinaPeptides Co. Ltd.), and anti-Gi2α (1:1000, Proteintech) antibodies.…”

Role of CRTC2 in Metabolic Homeostasis: Key Regulator of Whole-Body Energy Metabolism?

“…In addition, another recent study suggested a role of CRTC2 in controlling hepatic cholesterol metabolism. The authors demonstrated that CRTC2 is essential for activating the transcription of SREBP-2, a master regulator of cholesterol metabolism, via co-activation of CREB and inhibition of FoxO1 [27]. Furthermore, in conjunction with SREBP-2, CREB/CRTC2 has also been shown to enhance the transcription of HMG-CoA reductase, thus suggesting a critical role of CRTC2 in controlling hepatic cholesterol homeostasis.…”