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.

Aqueous or lipid components of atherosclerotic lesion increase macrophage oxidation and lipid accumulation

“…The lesion aqueous extracts hLAE and mAAE contained mainly proteins, phospholipids, and traces of free fatty acids, cholesterol and triglyceride [30], while mALE and hLLE were mainly composed of nonpolar lipids such as triglyceride [27] and cholesterol. We suppose that dividing the lesion to extracts and identifying each extract compounds (lipid or protein) is important for understanding the contribution of each compound to macrophage foam cell formation, the hallmark of early atherosclerosis (for the study design see Fig.…”

“…The reduction in cholesterol biosynthesis rate in the cells treated with the human lesion extracts could be attributed to changes in HMGCR expression level, the rate limiting enzyme for cholesterol biosynthesis [30,59,60]. High concentration of hLAE or hLLE significantly downregulated the HMGCR expression by 23% or 68%, respectively (Fig.…”

“…Previous studies from our lab evaluated the effects of different extracts from human atherosclerotic plaques on plasma and on cultured macrophages. Tavori et.al [27,28] and Cohen et.al [29][30][31] analyzed the biochemical composition of human carotid plaque extracts and their influence on the potent antioxidant paraoxonase1 (PON1) activity. Additionally, the effects of the non-polar hydrophobic lesion lipid extract (hLLE) on macrophages [mouse peritoneal macrophages (MPM), and J774A.1 murine macrophage cell line] was accessed.…”

Targeting macrophagic 17β-HSD7 by fenretinide for the treatment of nonalcoholic fatty liver disease

“…It was reported that cholesterol synthesis pathways were up-regulated in the macrophages of mice with metabolic diseases 13 , 14 , 15 . Another study showed that macrophages isolated from the liver of NAFLD mice were rich with free cholesterol 16 .…”

Human carotid atherosclerotic plaque protein(s) change HDL protein(s) composition and impair HDL anti‐oxidant activity

“…Plaque components are in direct contact with circulating blood elements and thus they could affect each other. Therefore, our ongoing research is focused on the mutual interaction between the human carotid plaque components and elements in the circulating blood [20][21][22][23][24][25]. A recent study showed that plaque PC specifically interacts with the HDL-bound enzyme PON1, increases its activity, and enhances its uptake by macrophages at the expense of its binding to the HDL [24].…”