Acetyl-CoA Deficiency Is Involved in the Regulation of Iron Overload on Lipid Metabolism in Apolipoprotein E Knockout Mice

Authors:
Open Access
Publisher website
Google Scholar
Abstract
The role of dietary iron supplementation in the development of nonalcoholic fatty liver disease (NAFLD) remains controversial. This study aimed to investigate the effect of excess dietary iron on NAFLD development and the underlying mechanism. Apolipoprotein E knockout mice were fed a chow diet, a high-fat diet (HFD), or an HFD containing 2% carbonyl iron (HFD + Fe) for 16 weeks. The serum and liver samples were acquired for biochemical and histopathological examinations. Isobaric tags for relative and absolute quantitation were performed to identify differentially expressed proteins in different groups. Excess dietary iron alleviated HFD-induced NAFLD, as evidenced by significant decreases in serum/the hepatic accumulation of lipids and the NAFLD scores in HFD + Fe-fed mice compared with those in HFD-fed mice. The hepatic acetyl-CoA level was markedly decreased in the HFD + Fe group compared with that in the HFD group. Important enzymes involved in the source and destination of acetyl-CoA were differentially expressed between the HFD and HFD + Fe groups, including the enzymes associated with cholesterol metabolism, glycolysis, and the tricarboxylic acid cycle. Furthermore, iron overload-induced mitochondrial dysfunction and oxidative stress occurred in mouse liver, as evidenced by decreases in the mitochondrial membrane potential and antioxidant expression. Therefore, iron overload regulates lipid metabolism by leading to an acetyl-CoA shortage that reduces cholesterol biosynthesis and might play a role in NAFLD pathogenesis. Iron overload-induced oxidative stress and mitochondrial dysfunction may impair acetyl-CoA formation from pyruvate and β-oxidation. Our study provides acetyl-CoA as a novel perspective for investigating the pathogenesis of NAFLD.
Funding Information
  • National Natural Science Foundation of China (82003460, 82103841, 2021JJ40814, 2021JJ40807, kq2014142)
  • Natural Science Foundation of Hunan Province (82003460, 82103841, 2021JJ40814, 2021JJ40807, kq2014142)
  • Changsha Municipal Natural Science Foundation (82003460, 82103841, 2021JJ40814, 2021JJ40807, kq2014142)

This publication has 39 references indexed in Scilit: