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KMID : 0620920190510090114
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Experimental & Molecular Medicine
2019 Volume.51 No. 9 p.114 ~ p.114
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Therapeutic effect of dichloroacetate against atherosclerosis via hepatic FGF21 induction mediated by acute AMPK activation
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Min Byong-Keol
Oh Chang-Joo
Park Sung-Mi
Lee Ji-Min
Go Young-Hoon
Park Bo-Yoon
Kang Hyeon-Ji
Kim Dong-Wook
Kim Jeong-Eun
Yoo Eun-Kyung
Kim Hui-Eon
Kim Mi-Jin
Jeon Yong-Hyun
Kim Yong-Hoon
Lee Chul-Ho
Jeon Jae-Han
Lee In-Kyu
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Abstract
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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 (PPARα). 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.
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KEYWORD
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Atherosclerosis, Dyslipidaemias
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