Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis

Han, Hye Sook; Choi, Byeong Hun; Kim, Jun Seok; Kang, Geon; Koo, Seung Hoi

doi:10.1038/s41467-017-01878-6

Cited by 49 publications

(49 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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. Proper restoration of TAC‐suppressed CRTC2 activation is of help to prevent and alleviate TAC‐induced metabolic disorders.…”

Section: Discussionsupporting

confidence: 91%

“…Canettieri et al found that rat hepatocytes with adenoviral overexpression of CRTC2 were more responsive to acute insulin stimulation, whereas mice with adenovirus CRTC2 RNAi showed almost undetectable IRS2 expression and reduced AKT phosphorylation in the liver. In contrast, other studies showed that either whole‐body or liver‐specific CRTC2 knockout mice presented markedly better glucose and insulin tolerance under high‐fat diet conditions but not in the chow‐fed state . Taken together, it seems that the role of CRTC2 in hepatic insulin sensitivity is dependent on certain circumstances (eg, diet and fatty liver).…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 86%

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

View full text Add to dashboard Cite

show abstract

“…Unlike in the previous studies, CRTC2-KO mice lacking the entire CRTC2 protein displayed reduced blood glucose levels and improved glucose tolerance compared with their wild-type littermates, which is consistent with the results of earlier acute knockdown studies. Indeed, we were able to confirm the results of the latter study by using liver-specific CRTC2-KO mice, and showing that CRTC2 is a crucial regulator of glucose metabolism by controlling hepatic gluconeogenesis in vivo [25].…”

Section: Glucose Metabolismsupporting

confidence: 76%

“…We have explored the role of CRTC2 in hepatic lipid metabolism by using liver-specific CRTC2-KO mice [25]. Unlike previous reports that used whole-body CRTC2-KO mice, we found that liver-specific depletion of CRTC2 ameliorates lipid accumulation in the liver under conditions of diet-induced obesity (DIO).…”

Section: Lipid Metabolismmentioning

confidence: 77%

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

2020

Self Cite

View full text Add to dashboard Cite

Cyclic adenosine monophosphate (cAMP) signaling is critical for regulating metabolic homeostasis in mammals. In particular, transcriptional regulation by cAMP response element-binding protein (CREB) and its coactivator, CREB-regulated transcription coactivator (CRTC), is essential for controlling the expression of critical enzymes in the metabolic process, leading to more chronic changes in metabolic flux. Among the CRTC isoforms, CRTC2 is predominantly expressed in peripheral tissues and has been shown to be associated with various metabolic pathways in tissue-specific manners. While initial reports showed the physiological role of CRTC2 in regulating gluconeogenesis in the liver, recent studies have further delineated the role of this transcriptional coactivator in the regulation of glucose and lipid metabolism in various tissues, including the liver, pancreatic islets, endocrine tissues of the small intestines, and adipose tissues. In this review, we discuss recent studies that have utilized knockout mouse models to delineate the role of CRTC2 in the regulation of metabolic homeostasis.

show abstract

“…Substrate switching and efficient nutrient utilization in the liver are key for maintaining metabolic homeostasis at the organismal level (Han et al, 2017;Rui, 2014). Specifically, SIRT1-PGC1a regulate glucose and fat metabolism in hepatocytes.…”

Section: Fed Micrornas Regulate Hepatic Fao and Organismal Energy Hommentioning

confidence: 99%

Loss of Hepatic Oscillatory Fed microRNAs Abrogates Refed Transition and Causes Liver Dysfunctions

et al. 2019

View full text Add to dashboard Cite

Graphical Abstract Highlights d Anticipatory hepatic fed miRNAs are essential to attenuating fasting response d RISC association of miRNA-mRNA pairs oscillates during fed-fast cycles in the liver d Convergent additive action of miRNAs governs metabolic and mitochondrial homeostasis d Scavenging fed miRNAs impairs refed transition and affects whole-body energetics SUMMARY Inability to mediate fed-fast transitions in the liver is known to cause metabolic dysfunctions and diseases. Intuitively, a failure to inhibit futile translation of state-specific transcripts during fed-fast cycles would abrogate dynamic physiological transitions.Here, we have discovered hepatic fed microRNAs that target fasting-induced genes and are essential for a refed transition. Our findings highlight the role of these fed microRNAs in orchestrating system-level control over liver physiology and whole-body energetics. By targeting SIRT1, PGC1a, and their downstream genes, fed microRNAs regulate metabolic and mitochondrial pathways. MicroRNA expression, processing, and RISC loading oscillate during these cycles and possibly constitute an anticipatory mechanism. Fed-microRNA oscillations are deregulated during aging. Scavenging of hepatic fed microRNAs causes uncontrolled gluconeogenesis and failure in the catabolic-to-anabolic switching upon feeding, which are hallmarks of metabolic diseases. Besides identifying mechanisms that enable efficient physiological toggling, our study highlights fed microRNAs as candidate therapeutic targets.

show abstract

Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis

Cited by 49 publications

References 40 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

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

Loss of Hepatic Oscillatory Fed microRNAs Abrogates Refed Transition and Causes Liver Dysfunctions

Contact Info

Product

Resources

About