Conjugated Linoleic Acid and Alpha Linolenic Acid Improve Cholesterol Homeostasis in Obesity by Modulating Distinct Hepatic Protein Pathways

Scope High‐fat diet (HFD)‐induced obesity impairs macrophage‐to‐feces reverse cholesterol transport (RCT). It is hypothesized that dietary supplementation with the polyunsaturated fatty acids conjugated linoleic acid (CLA) or alpha linolenic acid (ALA) would prevent HFD‐impaired RCT by modulating hepatic protein pathways. Methods and results ApoE3L.CETP mice are fed a HFD supplemented ± CLA or ALA for 12 weeks and in vivo macrophage‐to‐feces RCT is determined. Hepatic cholesterol transporters and the hepatic proteome are assessed by immunoblotting and mass spectrometry, respectively. Mice fed HFD alone, but not ALA‐HFD or CLA‐HFD, exhibit increased systemic cholesterol levels, increased 3H‐cholesterol levels in plasma and liver but not feces during RCT, and reduced hepatic ABCG5/8 expression relative to LFD. ALA‐HFD significantly reduces liver weight, hepatic cholesterol levels, and expression of the cholesterol synthesis enzyme farnesyl pyrophosphate synthase relative to HFD. ALA further increases the expression of acetyl‐coA oxidase‐associated proteins and suppress PPARα‐induced proteins relative to HFD. CLA does not significantly attenuate hepatic lipid levels but is associated with reduced hepatic expression of fatty acid binding protein (FABP)‐1/FABP4 levels relative to HFD, and reduced inflammatory pathway activation relative to ALA‐HFD. Conclusion ALA and CLA exert distinct mechanistic advantages on cholesterol homeostasis and RCT in obesity. Saturated‐fat‐induced obesity increases cholesterol levels due to reduced elimination. Here, it is demonstrated that supplementation of a saturated‐fat diet with polyunsaturated fats (ALA or CLA) reduces cholesterol levels, but does so by different pathways. ALA activates proteins involved in burning of fat (Acox1) and reduces proteins involved in cholesterol synthesis (FDPS), which are associated with reduced liver fat accumulation. CLA reduces cholesterol synthesis enzyme (HMG‐CoA reductase) and reduces inflammation, but does not affect liver fat levels.