铁超载加重非酒精性脂肪肝病过程中线粒体自噬的作用及其机制

doi:10.3969/j.issn.1004-616x.2025.04.016

摘要/Abstract

摘要： 目的：建立小鼠非酒精性脂肪肝病(NAFLD)模型，研究铁超载加重NAFLD发病过程中线粒体自噬的作用及其机制。方法：将72只雄性C57BL/6小鼠随机分成对照组、高铁组、高脂组、高铁高脂组共4个组，连续喂饲干预至实验结束，每组18只。分别于第8和第12周处死小鼠，进行血生化指标检测、肝组织病理学检测；采用Western blot法检测肝组织线粒体动力学相关因子(OPA1、DRP1)，自噬和线粒体自噬相关因子(PINK1、Parkin)的蛋白表达水平；并用反转录实时荧光定量PCR(RT-qPCR)方法检测PINK1、Parkin的mRNA表达水平。结果：与对照组相比，单纯高脂膳食可增加小鼠血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、甘油三酯(TG)和总胆固醇(TC)的含量(P<0.05)，使肝脏出现脂肪变性；高脂膳食降低肝组织线粒体融合蛋白OPA1的表达，增加线粒体分裂蛋白DRP1的表达，并降低线粒体自噬相关因子PINK1、Parkin蛋白和mRNA的表达水平(P<0.05)；高铁组在第8周和第12周时上调了肝组织线粒体相关因子OPA1蛋白及Parkin的mRNA表达水平(P<0.05)。高脂高铁联合饮食，使血清TG、ALT含量进一步增加，加重肝脏损伤(P<0.05)，影响肝组织线粒体自噬相关因子PINK1、Parkin蛋白和PINK、Parkin mRNA的表达。结论：高脂膳食能够成功诱导小鼠建立NAFLD模型。铁超载在NAFLD发生发展过程中能促进血脂升高和肝脏脂质沉积，加重肝脏功能和线粒体损伤，从而促进NAFLD病程进展。

关键词: 非酒精性脂肪肝, 自噬, 线粒体自噬, 炎症, 铁超载

Abstract: OBJECTIVE： To establish a mouse model of non-alcoholic fatty liver disease (NAFLD)，and to study the role and mechanism of mitochondrial autophagy in the pathogenesis of NAFLD aggravated by iron overload. METHODS： Seventy-two male C57BL/6 mice were randomly divided into control group，high iron group，high fat group，and high iron plus high fat group. The mice were fed continuously until the end of the experiment，with 18 mice in each group. The mice were sacrificed at the 8th and 12th weeks，respectively，and were subjected to blood biochemical indexes，liver histopathology；and protein expression levels of mitochondrial dynamicsrelated factors OPA1 and DRP1，autophagy and mitochondrial autophagy-related factors PINK1，Parkin which were detected by Western blot and the mRNA levels of PINK1 and Parkin were detected by real-time quantitative PCR (RT-qPCR). RESULTS： Compared with the control group，a simple high-fat diet significantly increased the levels of serum alanine aminotransferase (ALT)，aspartate aminotransferase (AST)，triglyceride(TG) and total cholesterol (TC) (P<0.05)，promoted hepatic steatosis， reduced the expression of mitochondrial fusion proteins OPA1，increased the expression of mitochondrial fission proteins DRP1，and reduced the expression levels of mitochondrial autophagy-related proteins and genes PINK1 and Parkin (P<0.05). The high-speed rail group upregulated the mRNA expression levels of mitochondrial related factor OPA1 protein and Parkin at weeks 8 and 12 (P<0.05). The combined effect of high-fat and high iron diet further increased serum TG and ALT levels，exacerbated liver damage (P<0.05)，and affected expressions of mitochondrial autophagy-related proteins PINK1 and Parkin，as well as genes PINK and Parkin. CONCLUSION： High-fat diets successfully induced the establishment of a NAFLD modeling in mice. Iron overload promoted elevation of blood lipids and hepatic lipid deposition during the occurrence and development of NAFLD，aggravated liver function and mitochondrial damage，thereby promoted the progression of NAFLD.

Key words: nonalcoholic fatty liver disease, autophagy, mitochondrial autophagy, inflammation, iron overloda

中图分类号:

R575

陈怡如, 王丽, 武鑫悦, 赵艳. 铁超载加重非酒精性脂肪肝病过程中线粒体自噬的作用及其机制[J]. 癌变·畸变·突变, 2025, 37(4): 319-323,329.

CHEN Yiru, WANG Li, WU Xinyue, ZHAO Yan. The role and mechanism of mitochondrial autophagy in the process of iron overload aggravating nonalcoholic fatty liver disease[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2025, 37(4): 319-323,329.

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