Dietary iron overload mitigates atherosclerosis in high-fat diet-fed apolipoprotein E knockout mice: Role of dysregulated hepatic fatty acid metabolism

The atherosclerosis iron hypothesis generates a fair amount of debate since it has been proposed. Here, we revisited the iron hypothesis by examining whether dietary iron overload would intensify iron deposition in plaques and thus lead to further exacerbation of atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice were fed either a normal chow diet (ND) or a high fat diet (HFD) supplemented with or without 2% carbonyl iron (Fe) for 16 weeks. However, contrary to our assumption, dietary iron overloading did not intensify, but rather diminished the atherosclerotic lesion area by 65.3%, which was accompanied by significantly decreased serum total cholesterol, triglyceride and low-density lipoprotein cholesterol contents, together with hepatic lipid accumulation decline, despite the evident existence of aortic iron accumulation and the typical signs of iron overload in ApoE KO mice. Using isobaric tag for absolute quantification (iTRAQ) proteomics approach, hepatic CD36 and fatty acid binding proteins-mediated fatty acid (FA) uptake and trafficking impairment were identified as the key potential pathomechanisms by which iron overload diminishes atherosclerotic lesions. Furthermore, downstream hepatic FA de novo biosynthesis was enhanced and FA oxidation was inhibited to compensate for the FA deficiency triggered by iron overload-impaired fatty acid uptake and trafficking. Our findings suggested that dietary iron overload is not atherogenic in ApoE KO mice, and more research efforts are warranted to revisit the iron hypothesis of atherosclerosis.

Automated summary

The study found that dietary iron overload did not exacerbate atherosclerosis in ApoE KO mice, but instead led to a reduction in lesion area by 65.3%. The research identified impaired fatty acid uptake and trafficking mediated by hepatic CD36 and fatty acid binding proteins as key mechanisms by which iron overload diminishes atherosclerotic lesions.