Dataset Information

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

ABSTRACT: Liver plays a crucial role in controlling energy homeostasis in mammals, although the exact mechanism by which it influences other peripheral tissues has yet to be addressed. Here we show that Creb regulates transcriptional co-activator (Crtc) 2 is a major regulator of whole-body energy metabolism. Crtc2 liver-specific knockout lowers blood glucose levels with improved glucose and insulin tolerance. Liver-specific knockout mice display increased energy expenditure with smaller lipid droplets in adipose depots. Both plasma and hepatic Fgf21 levels are increased in Crtc2 liver-specific knockout mice, as a result of the reduced miR-34a expression regulated by Creb/Crtc2 and the induction of Sirt1 and Ppar?. Ectopic expression of miR-34a reverses the metabolic changes in knockout liver. We suggest that Creb/Crtc2 negatively regulates the Sirt1/Ppar?/Fgf21 axis via the induction of miR-34a under diet-induced obesity and insulin-resistant conditions.

SUBMITTER: Han HS

PROVIDER: S-EPMC5709393 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Han Hye-Sook HS Choi Byeong Hun BH Kim Jun Seok JS Kang Geon G Koo Seung-Hoi SH

Nature communications 20171130 1

Liver plays a crucial role in controlling energy homeostasis in mammals, although the exact mechanism by which it influences other peripheral tissues has yet to be addressed. Here we show that Creb regulates transcriptional co-activator (Crtc) 2 is a major regulator of whole-body energy metabolism. Crtc2 liver-specific knockout lowers blood glucose levels with improved glucose and insulin tolerance. Liver-specific knockout mice display increased energy expenditure with smaller lipid droplets in ...[more]

PMID: 29192248

Similar Datasets

Project description:Background & Aims:Metabolism supports cell proliferation and growth. Surprisingly, the tumor suppressor miR-22 is induced by metabolic stimulators like bile acids. Thus, this study examines whether miR-22 could be a metabolic silencer. Methods:The relationship between miR-22 and the expression of fibroblast growth factor 21 (FGF21) and its receptor FGFR1 was studied in cells and fatty livers obtained from patients and mouse models. We evaluated the effect of an miR-22 inhibitor alone and in combination with obeticholic acid (OCA) for the treatment of steatosis. Results:The levels of miR-22 were inversely correlated with those of FGF21, FGFR1, and PGC1? in human and mouse fatty livers, suggesting that hepatic miR-22 acts as a metabolic silencer. Indeed, miR-22 reduced FGFR1 by direct targeting and decreased FGF21 by reducing the recruitment of PPAR? and PGC1? to their binding motifs. In contrast, an miR-22 inhibitor increases hepatic FGF21 and FGFR1, leading to AMPK and ERK1/2 activation, which was effective in treating alcoholic steatosis in mouse models. The farnesoid x receptor-agonist OCA induced FGF21 and FGFR1, as well as their inhibitor miR-22. An miR-22 inhibitor and OCA were effective in treating diet-induced steatosis, both alone and in combination. The combined treatment was the most effective at improving insulin sensitivity, releasing glucagon-like peptide 1, and reducing hepatic triglyceride in obese mice. Conclusion:The simultaneous induction of miR-22, FGF21 and FGFR1 by metabolic stimulators may maintain FGF21 homeostasis and restrict ERK1/2 activation. Reducing miR-22 enhances hepatic FGF21 and activates AMPK, which could be a novel approach to treat steatosis and insulin resistance. Lay summary:This study examines the metabolic role of a tumor suppressor, miR-22, that can be induced by metabolic stimulators such as bile acids. Our novel data revealed that the metabolic silencing effect of miR-22 occurs as a result of reductions in metabolic stimulators, which likely contribute to the development of fatty liver. Consistent with this finding, an miR-22 inhibitor effectively reversed both alcohol- and diet-induced fatty liver; miR-22 inhibition is a promising therapeutic option which could be used in combination with obeticholic acid.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets