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Inducible phospholipid transfer protein deficiency ameliorates atherosclerosis

      Highlights

      • Inducible phospholipid transfer protein (PLTP) deficiency reduces plasma cholesterol levels and very low-density lipoproteins (VLDL) production.
      • Inducible PLTP deficiency attenuates AAV8-PCSK9- and Western-type diet-induced atherosclerosis progression.
      • Poor regression of atherosclerotic plaques after low-density lipoprotein cholesterol lowering in mice can be overcome by PLTP depletion.
      • Inhibiting PLTP in patients with atherosclerosis could be an effective approach for the treatment of the disease.

      Abstract

      Background and aims

      Atherosclerosis progression and regression studies are related to its prevention and treatment. Although we have gained extensive knowledge on germline phospholipid transfer protein (PLTP) deficiency, the effect of inducible PLTP deficiency in atherosclerosis remains unexplored.

      Methods

      We generated inducible PLTP (iPLTP)-knockout (KO) mice and measured their plasma lipid levels after feeding a normal chow or a Western-type diet. Adenovirus associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9) was used to induce hypercholesterolemia in the mice. Collars were placed around the common carotid arteries, and atherosclerosis progression and regression in the carotid arteries and aortic roots were evaluated.

      Results

      On a normal chow diet, iPLTP-KO mice exhibited decreased cholesterol, phospholipid, apoA-I, and apoB levels compared with control mice. Furthermore, the overall amount of high-density lipoprotein (HDL) particles was reduced in these mice, but this effect was more profound for larger HDL particles. On a Western-type diet, iPLTP-KO mice again exhibited reduced levels of all tested lipids, even though the basal lipid levels were increased. Additionally, these mice displayed significantly reduced atherosclerotic plaque sizes with increased plaque stability. Importantly, inducible PLTP deficiency significantly ameliorated atherosclerosis by reducing the size of established plaques and the number of macrophages in the plaques without causing lipid accumulation in the liver.

      Conclusions

      Induced PLTP deficiency in adult mice reduces plasma total cholesterol and triglycerides, prevents atherosclerosis progression, and promotes atherosclerosis regression. Thus, PLTP inhibition is a promising therapeutic approach for atherosclerosis.

      Graphical abstract

      Keywords

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