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

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Abstract

Recent ACC/AHA guidelines recommend ≥ 5% weight loss over 6 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 proatherogenic lipid remodeling. ApoE-deficient mice were fed Chow or a high-cholesterol/high-fat (HCHF) diet for 6 months, with MfR producing 5% lower body-weight gain. Atherosclerotic burden was quantified histologically, and hepatic lipidomes were analyzed by electrospray ionization tandem mass spectrometry (ESI-MS/MS) and compared with plasma lipidomic profiles from patients with CVD. 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/media ratios, and inflammatory cell infiltration. Similar proatherogenic changes occurred in Chow-fed mice subjected to MfR. Mechanistically, MfR increased hepatic free cholesterol and enriched proatherogenic 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 patients with CVD with diabetes. Collectively, our findings demonstrate that mild caloric restriction is not universally atheroprotective and can accelerate atherosclerosis in hypercholesterolemic states by disrupting cholesterol homeostasis and promoting proatherogenic lipid remodeling.

Authors

Yun Zhu, Yanzhe Xu, Gerhard Liebisch, Juergen Borlak