Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2

Hogan, Meghan F.; Ravnskjær, Kim; Matsumura, Shigenobu; Huising, Mark O.; Hull, Rebecca L.; Kahn, Steven E.; Montminy, Marc

doi:10.1074/jbc.m115.679266

Cited by 29 publications

(26 citation statements)

References 34 publications

(29 reference statements)

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“…Taken together, it seems that the role of CRTC2 in hepatic insulin sensitivity is dependent on certain circumstances (eg, diet and fatty liver). Acute or chronic, overactivated or deactivated CRTC2 may have various effects on hepatic insulin signaling . We agreed with the conclusion from Han et al that tight regulation of hepatic CRTC2 function is critical in the maintenance of energy and metabolic homeostasis in mammals.…”

Section: Discussionsupporting

confidence: 91%

The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside

Ling

Huang

Han

et al. 2020

American Journal of Transplantation

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Tacrolimus (TAC), the mainstay of maintenance immunosuppressive agents, plays a crucial role in new‐onset diabetes after transplant (NODAT). Previous studies investigating the diabetogenic effects of TAC have focused on the β cells of islets. In this study, we found that TAC contributed to NODAT through directly affecting hepatic metabolic homeostasis. In mice, TAC‐induced hypoglycemia rather than hyperglycemia during starvation via suppressing gluconeogenetic genes, suggesting the limitation of fasting blood glucose in the diagnosis of NODAT. In addition, TAC caused hepatic insulin resistance and triglyceride accumulation through insulin receptor substrate (IRS)2/AKT and sterol regulatory element binding protein (SREBP1) signaling, respectively. Furthermore, we found a pivotal role of CREB‐regulated transcription coactivator 2 (CRTC2) in TAC‐induced metabolic disorders. The restoration of hepatic CRTC2 alleviated the metabolic disorders through its downstream molecules (eg, PCK1, IRS2, and SREBP1). Consistent with the findings from bench, low CRTC2 expression in graft hepatocytes was an independent risk factor for NODAT (odds ratio = 2.692, P = .023, n = 135). Integrating grafts’ CRTC2 score into the clinical model could significantly increase the predictive capacity (areas under the receiver operating characteristic curve: 0.71 vs 0.79, P = .048). Taken together, in addition to its impact on pancreatic cells, TAC induces “hematogenous diabetes” via CRTC2 signaling. Liver‐targeted management may be of help to prevent or heal TAC‐associated diabetes.

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Section: Discussionsupporting

confidence: 91%

The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside

Ling

Huang

Han

et al. 2020

American Journal of Transplantation

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“…Previous reports have shown that CRTC2 has different effects on lipid metabolism under different conditions . For example, on a chow diet, the chronic overexpression of CRTC2 activated CRTC2‐induced hepatic steatosis and higher levels of hepatic TG, as expected in hyperglycemia .…”

Section: Discussionmentioning

confidence: 88%

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

Song

Zhao

et al. 2017

Hepatology

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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).

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“…Consistent with this crosstalk, the CREB–CBP–CRTC2 module exerts stronger control over the expression of G6pc during the first 6 h of fasting in mice, whereas the FOXO1–PGC1α module has a larger role in stimulating G6pc transcription over longer durations (~18 h) of fasting in mice 116 . As predicted, Crtc2 –knockout mice had fasting hypoglycaemia and mice with adeno-associated virus (AAV)-mediated overexpression of constitutively active CRTC2 were hyperglycaemic 117,118 .…”

Section: Control Of Hepatic Gluconeogenesismentioning

confidence: 59%

Regulation of hepatic glucose metabolism in health and disease

2017

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The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis.

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Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2

Cited by 29 publications

References 34 publications

The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside

The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside

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

Regulation of hepatic glucose metabolism in health and disease

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