Mild caloric restriction accelerates atherosclerosis via dysregulated cholesterol homeostasis and lipogenesis in HCHF-fed ApoE-deficient mice

Recent ACC/AHA guidelines recommend ≥5% weight loss over six months to reduce cardiovascular risk in obesity. However, some populations paradoxically exhibit increased cardiovascular disease (CVD) following weight loss. We investigated whether mild food restriction (MfR) accelerates atherogenesis through pro-atherogenic lipid remodelling. ApoE-deficient mice were fed Chow or a high-cholesterol/high-fat(HCHF) diet for six months, with MfR producing 5% lower body-weight gain. Atherosclerotic burden was quantified histologically, and hepatic lipidomes were analysed by ESI–MS/MS and compared with plasma lipidomic profiles from CVD patients. MfR improved insulin sensitivity by lowering blood glucose and triglycerides but increased circulating cholesterol and accelerated atherosclerosis. HCHF-fed mice developed larger, more numerous plaques with increased necrotic core formation, thinner fibrous caps, higher intima-to-media ratios, and inflammatory cell infiltration. Similar pro-atherogenic changes occurred in Chow-fed mice subjected to MfR. Mechanistically, MfR increased hepatic free cholesterol and enriched pro-atherogenic phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine, sphingomyelin, ceramide, and cholesterol ester species, yielding a CERT1 score of 8.1 indicative of cardiovascular risk. These lipid alterations mirrored plasma lipidomic signatures from CVD patients with diabetes. Collectively, our findings demonstrate that mild caloric restriction is not universally atheroprotective and can accelerate atherosclerosis in hypercholesterolaemic states by disrupting cholesterol homeostasis and promoting pro-atherogenic lipid remodelling.

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