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 (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.
Highlights
Excess nutrient-induced dyslipidemia and diabetes are significantly associated with cardiovascular diseases, including atherosclerosis and coronary artery disease[1]
We report that DCA systematically ameliorates atherosclerosis via FGF21-mediated enhanced energy expenditure in an AMPK-dependent manner, which was confirmed by increased glucose uptake associated with enhanced energy expenditure
The significant increase in the low-density lipoprotein (LDL) level by western diet (WD) was reduced by DCA treatment in a dose-dependent manner, while the reduced high-density lipoprotein (HDL) and increased VLDL levels were not altered by DCA treatment among DCAtreated and WD control mice (Fig. 1e)
Summary
Excess nutrient-induced dyslipidemia and diabetes are significantly associated with cardiovascular diseases, including atherosclerosis and coronary artery disease[1]. Many studies have demonstrated that fibroblast growth factor (FGF) 21 is a therapeutic agent for the treatment of obesity-related diseases, including atherosclerosis, which increases lipoprotein uptake and catabolism[9,10,11] It is secreted predominantly by the liver, is upregulated by starvation, the consumption of a ketogenic diet, and amino acid deprivation via peroxisome proliferator- activated receptor alpha (PPARα)- or activating transcription factor 4 (ATF4)-dependent mechanisms, and binds to FGF receptor 1 and β-Klotho. This leads to increases in thermogenic genes, the β-oxidation of lipids and the metabolic rate through PPAR gamma coactivator 1α (PGC1α) in BAT12,13. The collective findings indicate that FGF21 has a mitohormetic effect in response to various metabolic disorders that are positively associated with mitochondrial dysfunction in adaptive thermogenesis
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