title: Human carotid atherosclerotic lesion protein components decrease cholesterol biosynthesis rate in macrophages through 3-hydroxy-3-methylglutaryl-CoA reductase regulation.
abstract: Atherosclerosis is characterized by the formation of cholesterol-loaded macrophages, which are turned into foam cells, the hallmark of early atherogenesis. As part of ongoing research on the interactions among human carotid lesion components and blood elements, the effect of plaque homogenate on macrophage cholesterol biosynthesis rate was examined. Human carotid plaques were ground, extracted with phosphate-buffered saline (homogenate), and then added to the macrophage medium. This extract decreased macrophage cholesterol biosynthesis rate up to 50% in a dose-dependent manner. Cholesterol or lipoproteins were separated from the homogenate and added to the MQ medium. Unlike the homogenate, neither free cholesterol nor the lipoproteins were able to inhibit cholesterol biosynthesis rate under the above experimental concentration, suggesting that the homogenate-induced cholesterol biosynthesis inhibition in our experimental system was not owing to the feedback inhibition of cholesterol. Furthermore, the homogenate remaining after lipoprotein removal (lipoprotein-deficient homogenate) also decreased cholesterol biosynthesis rate, whereas boiled homogenate or phospholipids extracted from the homogenate decreased macrophage cholesterol biosynthesis rate only partially. Finally, cholesterol biosynthesis inhibition was achieved only upon using the precursor [(3)H]acetate, but not [(14)C]mevalonate, suggesting that 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA Reductase), the rate-limiting enzyme in the cholesterol biosynthesis pathway, is involved in the above antiatherogenic effect of the homogenate, whereas the treatment with homogenate decreased HMGCoA Reductase mRNA. Proteins and phospholipids from human carotid lesion homogenate decrease cholesterol biosynthesis rate in macrophages secondary to HMGCoA Reductase feedback regulation. Such an effect may delay foam cell formation and atherosclerosis progression.
authors: Department of Oxidative Stress and Human Diseases, MIGAL-Galilee Research Institute, Kiryat Shmona, Tel Hai College, Israel; The Lipid Research Laboratory, the Technion Rappaport Faculty of Medicine and Research Institute, Rambam Health Care Campus, Technion- Israel Institute of Technology, Haifa, Israel.
authors: Elad
authors: E
authors: Cohen
authors: Michael
authors: M
authors: Aviram
authors: Soliman
authors: S
authors: Khatib
authors: Mira
authors: M
authors: Rosenblat
authors: Jacob
authors: J
authors: Vaya
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000737:chemistry / Q000473:pathology; D002460:Cell Line; D005591:Chemical Fractionation; D002784:Cholesterol / Q000096:biosynthesis; D045424:Complex Mixtures / Q000032:analysis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000302:isolation & purification / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D058226:Plaque, Atherosclerotic / Q000737:chemistry* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D045424:Complex Mixtures; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: HMGCoA reductase; atherosclerosis; atherosclerotic lesion; cholesterol biosynthesis; plaque