Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis But Elevates Plasma Triglycerides in Mic

This suggests that the tgs normally destined for

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This suggests that the TGs normally destined for incorporation into VLDL for secretion were oxidized once PPAR α activity was restored in ACC dLKO mice, even though GPAT1 mRNA levels in ACC dLKO mice remained elevated (data not shown). As described above, how the channeling of fatty acids between oxidation and secretion is regulated is not known but the localization of GPAT1 to the mitochondrial membrane opens the possibility that GPAT1 cooperates/interacts with CPT1 to regulate this channeling. Previous reports suggested that plasma TG levels are increased following ACC inhibition. The germline deletion of ACC2 resulted in increased plasma TGs (Abu-Elheiga et al., 2001). It was suggested in this report that the increased serum TGs were due to the mobilization of TGs from peripheral organs due to the lack of malonyl-CoA, although no mechanistic studies were reported. However, a recent study by Harriman et al . (Harriman et al., 2016) reported the effects of ACC inhibition in rats using ND-630, an allosteric inhibitor of ACC dimerization. Consistent with the studies reported in this report, they found that ACC inhibition in DIO and Zucker diabetic rats significantly reduced liver TG content but also increased insulin sensitivity. In contrast to our studies in mice and humans, they found plasma TGs decreased after administration of the ACC inhibitor. The reason for the discrepancy is not clear at this time. It is possible the rat responds differently to ACC inhibition than mice and humans, that inhibition of ACC in peripheral tissues as well as liver results in changes that increase plasma VLDL clearance or catabolism, or that the ND-630 does not inhibit ACC activity to the same degree as MK-4074. Additional studies will be required to resolve this important issue. The results reported here show for the first time that the inhibition of ACC in humans can significantly reduce liver TGs and that alternative strategies to reduce lipogenesis that also enhance FAO might be beneficial for the treatment of NAFLD. Unfortunately, we found liver inhibition of ACC resulted in a relative deficiency of PUFAs, which led to the activation of SREBP-1c, elevated GPAT1 expression, and hypertriglyceridemia. It may be Kim et al. Page 11 Cell Metab . Author manuscript; available in PMC 2018 August 01. Author Manuscript Author Manuscript Author Manuscript Author Manuscript
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that not all individuals with NAFLD who are administered an ACC inhibitor will manifest significant hypertriglyceridemia and the degree of hypertriglyceridemia may be modulated by the amount of PUFAs ingested or the individuals propensity to develop hypertriglyceridemia; however, the resulting activation of SREBP-1c, which also induced PNPLA3 expression could also be detrimental to those who carry the PNPLA3 polymorphism associated with NAFLD and cirrhosis. Combined, the findings of elevated plasma TGs and elevated PNPLA3 expression likely precludes the use of a liver-specific ACC inhibitors for the treatment of NAFLD. Although, the demonstration that inhibiting
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  • Winter '19
  • Robert S Kiss
  • Essential fatty acid, Fatty acid metabolism, Fatty liver

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