Department of Health Toxicology, Xiangya School of Public Health, Central South University, Changsha 410078, China.
Department of Nutrition Science and Food Hygiene, Xiangya School of Public Health, Central South University, Changsha 410078, China.
Molecules. 2022 Aug 4;27(15):4966. doi: 10.3390/molecules27154966.
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.
膳食铁补充剂在非酒精性脂肪性肝病（NAFLD）发展中的作用仍存在争议。本研究旨在探讨过量膳食铁对 NAFLD 发展的影响及其潜在机制。载脂蛋白 E 基因敲除小鼠分别喂食标准饲料、高脂肪饲料（HFD）或含 2%羰基铁的高脂肪饲料（HFD+Fe）16 周。采集血清和肝脏样本进行生化和组织病理学检查。采用等重标记相对和绝对定量技术鉴定不同组间差异表达的蛋白质。过量膳食铁可减轻 HFD 诱导的 NAFLD，与 HFD 组相比，HFD+Fe 组小鼠血清/肝脏脂质蓄积和 NAFLD 评分显著降低。与 HFD 组相比，HFD+Fe 组小鼠肝乙酰辅酶 A 水平显著降低。HFD 和 HFD+Fe 组间乙酰辅酶 A 来源和去向的重要酶表达存在差异，包括与胆固醇代谢、糖酵解和三羧酸循环相关的酶。此外，铁过载诱导的线粒体功能障碍和氧化应激发生在小鼠肝脏中，表现为线粒体膜电位和抗氧化剂表达降低。因此，铁过载通过导致乙酰辅酶 A 短缺来调节脂质代谢，从而减少胆固醇生物合成，并可能在 NAFLD 发病机制中发挥作用。铁过载诱导的氧化应激和线粒体功能障碍可能会损害来自丙酮酸和β氧化的乙酰辅酶 A 的形成。本研究为研究 NAFLD 的发病机制提供了乙酰辅酶 A 这一新视角。
