Mechanisms
CETP expression in bone-marrow-derived immune cells reduces inflammatory features of atherosclerosis, helping explain trial failures (Biomolecules 2023)
Original title: CETP Expression in Bone-Marrow-Derived Cells Reduces the Inflammatory Features of Atherosclerosis in Hypercholesterolemic Mice
Although CETP activity lowers plasma HDL cholesterol, a correlate of atherosclerosis risk, the authors' recent work suggested CETP expression in macrophages instead promotes an intracellular antioxidant state and reduces inflammation. To test whether this matters for disease, they transplanted bone marrow from mice expressing simian CETP, or non-expressing littermates, into hypercholesterolemic LDL-receptor-deficient mice. CETP expression did not change lesion area but decreased macrophage content, neutrophil accumulation, and TNF-alpha in the aorta of young males, and decreased neutrophil markers, TNF-alpha, iNOS, and nitrotyrosine in aged females. The findings show CETP expression in bone-marrow-derived cells reduces inflammatory features of atherosclerosis, offering a novel mechanistic explanation for why CETP inhibitors have failed to reduce atherosclerotic events in humans.
Original abstract
CETP activity reduces plasma HDL-cholesterol concentrations, a correlate of an increased risk of atherosclerotic events. However, our recent findings suggest that CETP expression in macrophages promotes an intracellular antioxidant state, reduces free cholesterol accumulation and phagocytosis, and attenuates pro-inflammatory gene expression. To determine whether CETP expression in macrophages affects atherosclerosis development, we transplanted bone marrow from transgenic mice expressing simian CETP or non-expressing littermates into hypercholesterolemic LDL-receptor-deficient mice. The CETP expression did not change the lipid-stained lesion areas but decreased the macrophage content (CD68), neutrophil accumulation (LY6G), and TNF-α aorta content of young male transplanted mice and decreased LY6G, TNF-α, iNOS, and nitrotyrosine (3-NT) in aged female transplanted mice. These findings suggest that CETP expression in bone-marrow-derived cells reduces the inflammatory features of atherosclerosis. These novel mechanistic observations may help to explain the failure of CETP inhibitors in reducing atherosclerotic events in humans.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.