The Roles of Lipoproteins, Diet, and Peripheral Macrophages in Atherosclerotic Disease

The Roles of Lipoproteins, Diet, and Peripheral Macrophages in Atherosclerotic Disease

Harry C Blair, Dionysios J Papachristou, Irina Tourkova, Lisa J Robinson, Jorge Sepulveda

Abstract


We consider lipid accumulation in atherosclerosis, with emphasis on mechanisms mediating atheroma growth at peripheral sites. Macrophages normally recycle all dead cell components, including membranes. Membrane lipids are exported, as cholesterol or cholesterol esters, by lipoproteins for disposal by the liver or, as triglycerides or phospholipids, for lipid storage or re-use. Membranes of somatic cells, such as red blood cells, incorporate fatty acids that reflect dietary intake. When excessive saturated and trans-unsaturated fats are incorporated in cells, and the cells die, macrophages cannot fully recycle the membrane lipids, setting up a vicious cycle of lipid overload, cell death, recruitment of macrophages, and cell proliferation. Semi-liquid masses of partially oxidized fatty acids and cholesterol, foamy macrophages, and proliferating stromal cells accumulate in arterial walls. The dramatic increase of atherosclerotic disease since 1920 reflects superabundant nutrition and altered dietary composition, along with reduced exercise and smoking. The dietary changes included increased saturated and trans-unsaturated fats. The biochemical basis of epidemic atherosclerosis includes a partial metabolic block in β-oxidation caused by unsaturated fatty acid intermediates. Responses of cells to un-degraded saturated and trans-fatty acids include production of inflammatory cytokines, alteration of macrophage signaling pathways, and altered lipid-handling enzymes. Prevention of disease is an ideal approach, but pharmacological inhibitors including statins, PCSK9 inhibitors, or limiting macrophage catabolism of lipids by reducing carnitine availability, may limit progression of atherosclerosis.

Keywords


Atherogenesis; cholesterol synthesis; HDL, LDL; type 1 macrophage; foam cell, Fcγ; PCSK9; statin.

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