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 (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.

Loss of metabolic flexibility as a result of overexpression of pyruvate dehydrogenase kinases in muscle, liver and the immune system: Therapeutic targets in metabolic diseases

“…As in PDK knockout mice, DCA is effective in promoting glucose oxidation and lowering blood glucose in diabetes 75 , which is supported by recent evidence that DCA can exert a metformin‐like effect by promoting AMPK activation 14,73 . DCA also lowers cAMP accumulation, which was increased in db / db mice liver compared with db /+ mice 14 .…”

“…In Western diet‐fed apolipoprotein E ( ApoE ) −/− mice, DCA stimulates hepatic fibroblast growth factor 21 ( fgf21 ) messenger ribonucleic acid expression in an AMP‐activated protein kinase‐dependent manner. The increase was sufficient to increase serum FGF21 level and subsequent activity of BAT 73 (Figure 2c). Furthermore, an unbiased [U‐ 13 C]‐glucose tracer‐based metabolomics study showed that PDC flux activity is decreased, whereas Ser293 p‐PDC level is decreased on β3‐adrenergic activation in brown adipocyte 74 .…”

“…The aforementioned pleiotropic effects of PDK inhibition, including targeting macrophage polarization, restoration of muscle glucose tolerance and suppression of hepatic glucose production, as well as prevention of non‐alcoholic fatty liver disease or non‐alcoholic steatohepatitis, have raised the possibility of a PDK inhibitor as a therapeutic option for metabolic syndrome. Furthermore, we recently observed that DCA increases brown adipose tissue (BAT) 73 . In Western diet‐fed apolipoprotein E ( ApoE ) −/− mice, DCA stimulates hepatic fibroblast growth factor 21 ( fgf21 ) messenger ribonucleic acid expression in an AMP‐activated protein kinase‐dependent manner.…”

PDK4 promotes vascular calcification by interfering with autophagic activity and metabolic reprogramming

“…Mice deficient for PDK4 in VSMCs exhibit a significant reduction in aortic calcium accumulation after vitamin D3 treatment compared with this accumulation in the control mice 22 . In ApoE −/− mice, inhibition of PDK4 by dichloroacetate (DCA), a wellestablished PDK inhibitor, attenuates atherosclerosis 23 . Recent studies from our laboratory and others have found that PDK4 activity is closely related to mitochondrial function in VSMCs 9,22 ; however, the exact mechanisms by which it affects pathological processes are poorly understood.…”

Aqueous extracts of Aconite promote thermogenesis in rats with hypothermia via regulating gut microbiota and bile acid metabolism

“…BAs play a key functional role in the regulation of thermogenesis. The primary BAs (PBAs) such as cholic acid (CA) and secondary BAs (SBAs, metabolites derived from gut microbiota) such as deoxycholic acid (DCA) can increase the expression of UCP1 in WAT and BAT, and promote WAT browning and BAT thermogenesis [23,24]. In rodents, browning of WAT and adaptive thermogenesis of BAT are the major contributors to the enhancement of energy metabolism [25].…”