title: Nature and nurture in atherosclerosis: The roles of acylcarnitine and cell membrane-fatty acid intermediates.
abstract: Macrophages recycle components of dead cells, including cell membranes. When quantities of lipids from cell membranes of dead cells exceed processing capacity, phospholipid and cholesterol debris accumulate as atheromas. Plasma lipid profiles, particularly HDL and LDL cholesterol, are important tools to monitor atherosclerosis risk. Membrane lipids are exported, as triglycerides or phospholipids, or as cholesterol or cholesterol esters, via lipoproteins for disposal, for re-use in cell membranes, or for fat storage. Alternative assays evaluate other aspects of lipid pathology. A key process underlying atherosclerosis is backup of macrophage fatty acid catabolism. This can be quantified by accumulation of acylcarnitine intermediates in extracellular fluid, a direct assay of adequacy of β-oxidation to deal with membrane fatty acid recycling. Further, membranes of somatic cells, such as red blood cells (RBC), incorporate fatty acids that reflect dietary intake. Changes in RBC lipid composition occur within days of ingesting modified fats. Since diets with high saturated fat content or artificial trans-fatty acids promote atherosclerosis, RBC lipid content shifts occur with atherosclerosis, and can show cellular adaptation to pathologically stiff membranes by increased long-chain doubly unsaturated fatty acid production. Additional metabolic changes with atherosclerosis of potential utility include inflammatory cytokine production, modified macrophage signaling pathways, and altered lipid-handling enzymes. Even after atherosclerotic lesions appear, approaches to minimize macrophage overload by reducing rate of fat metabolism are promising. These include preventive measures, and drugs including statins and the newer PCSK9 inhibitors. New cell-based biochemical and cytokine assays provide data to prevent or monitor atherosclerosis progression.
authors.affiliation: Pittsburgh VA Medical Center, Pittsburgh, PA 15261, United States; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, United States. Electronic address: hcblair@pitt.edu.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Blair
authors.affiliation: Department of Pathology & Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, United States.
authors.forename: Jorge
authors.initials: J
authors.lastname: Sepulveda
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, United States; Department of Anatomy-Histology-Embryology, Unit of Bone and Soft Tissue Studies, University of Patras Medical School, Patras, Greece. Electronic address: papachristoudj@med.upatras.gr.
authors.forename: Dionysios J
authors.initials: DJ
authors.lastname: Papachristou
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000473:pathology*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects; D018450:Disease Progression; D004912:Erythrocytes / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D008055:Lipids; C116917:acylcarnitine; D002331:Carnitine
keywords: Atherogenesis; Carnitine; Cholesterol synthesis; Coenzyme A; Fcγ; HDL; LDL; PCSK9; Statin