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Therapeutic effect of dichloroacetate against atherosclerosis via hepatic FGF21 induction mediated by acute AMPK activation.

ABSTRACT: Dyslipidemia-induced atherosclerosis, which has a risk of high morbidity and mortality, can be alleviated by metabolic activation associated with mitochondrial function. The effect of dichloroacetate (DCA), a general pyruvate dehydrogenase kinase (PDK) inhibitor, on in vivo energy expenditure in ApoE^-/- mice fed a western diet (WD) has not yet been investigated. WD-fed ApoE^-/- mice developed atherosclerotic plaques and hyperlipidemia along with obesity, which were significantly ameliorated by DCA administration. Increased oxygen consumption was associated with heat production in the DCA-treated group, with no change in food intake or physical activity compared with those of the control. These processes were correlated with the increased gene expression of Dio2 and Ucp-1, which represents brown adipose tissue (BAT) activation, in both WD-induced atherosclerosis and high-fat-induced obesity models. In addition, we found that DCA stimulated hepatic fibroblast growth factor 21 (Fgf21) mRNA expression, which might be important for lowering lipid levels and insulin sensitization via BAT activation, in a dose- and time-dependent manner associated with serum FGF21 levels. Interestingly, Fgf21 mRNA expression was mediated in an AMP-activated protein kinase (AMPK)-dependent manner within several minutes after DCA treatment independent of peroxisome proliferator-activated receptor alpha (PPAR?). Taken together, the results suggest that enhanced glucose oxidation by DCA protects against atherosclerosis by inducing hepatic FGF21 expression and BAT activation, resulting in augmented energy expenditure for heat generation.

SUBMITTER: Min BK

PROVIDER: S-EPMC6802614 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Therapeutic effect of dichloroacetate against atherosclerosis via hepatic FGF21 induction mediated by acute AMPK activation.

Min Byong-Keol BK Oh Chang Joo CJ Park Sungmi S Lee Ji-Min JM Go Younghoon Y Park Bo-Yoon BY Kang Hyeon-Ji HJ Kim Dong Wook DW Kim Jeong-Eun JE Yoo Eun Kyung EK Kim Hui Eon HE Kim Mi-Jin MJ Jeon Yong Hyun YH Kim Yong-Hoon YH Lee Chul-Ho CH Jeon Jae-Han JH Lee In-Kyu IK

Experimental & molecular medicine 20190930 10

Dyslipidemia-induced atherosclerosis, which has a risk of high morbidity and mortality, can be alleviated by metabolic activation associated with mitochondrial function. The effect of dichloroacetate (DCA), a general pyruvate dehydrogenase kinase (PDK) inhibitor, on in vivo energy expenditure in ApoE<sup>-/-</sup> mice fed a western diet (WD) has not yet been investigated. WD-fed ApoE<sup>-/-</sup> mice developed atherosclerotic plaques and hyperlipidemia along with obesity, which were significa ...[more]

PMID: 31570705

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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

Therapeutic effect of dichloroacetate against atherosclerosis via hepatic FGF21 induction mediated by acute AMPK activation.

Publications

Therapeutic effect of dichloroacetate against atherosclerosis via hepatic FGF21 induction mediated by acute AMPK activation.

Similar Datasets

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