Adipocyte-Derived Plasma Protein, Adiponectin, Suppresses Lipid Accumulation and Class A Scavenger Receptor Expression in Human Monocyte-Derived Macrophages

Abstract

Background-Excessive lipid accumulation in macrophages plays an important role in the development of atherosclerosis.Recently, we discovered an adipocyte-specific plasma protein, adiponectin, that is decreased in patients with coronary artery disease. We previously demonstrated that adiponectin acts as a modulator for proinflammatory stimuli and inhibits monocyte adhesion to endothelial cells. The present study investigated the effects of adiponectin on lipid accumulation in human monocyte-derived macrophages. Methods and Results-Human monocytes were differentiated into macrophages by incubation in human type AB serum for 7 days, and the effects of adiponectin were investigated at different time intervals. Treatment with physiological concentrations of adiponectin reduced intracellular cholesteryl ester content, as determined using the enzymatic, fluorometric method. The adiponectin-treated macrophages contained fewer lipid droplets stained by oil red O. Adiponectin suppressed the expression of the class A macrophage scavenger receptor (MSR) at both mRNA and protein levels by Northern and immunoblot analyses, respectively, without affecting the expression of CD36, which was quantified by flow cytometry. Adiponectin reduced the class A MSR promoter activity, as measured by luciferase reporter assay. Adiponectin treatment dose-dependently decreased class A MSR ligand binding and uptake activities. The mRNA level of lipoprotein lipase as a marker of macrophage differentiation was decreased by adiponectin treatment, but that of apolipoprotein E was not altered. Adiponectin was detected around macrophages in the human injured aorta by immunohistochemistry. Conclusions-The adipocyte-derived plasma protein adiponectin suppressed macrophage-to-foam cell transformation, suggesting that adiponectin may act as a modulator for macrophage-to-foam cell transformation.

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

“…In mice, the deletion of the adiponectin gene is associated with insulin resistance and neointimal hyperplasia [38]. Further, in vitro adiponectin inhibits monocyte adhesion to endothelial cells likely by reducing the TNF-α mediated inflammatory response [68] and decreasing macrophage to foam cell transformation [69]. Thus, it is possible that decreased adiponectin concentrations play a critical role in the pathogenesis of atherosclerosis via various mechanisms.…”

Hypoadiponectinaemia and high risk of type 2 diabetes are associated with adiponectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity

“…Given the worldwide epidemic of the onset of obesity at an early age, it is likely that the contribution of adiponectin in diabesity will tend to increase. In this context, taking into account ACDC variants and adiponectin levels, in assessing further risk of type 2 diabetes and premature CHD [5] may more effectively encourage subjects who could benefit from help in the future to prevent the diseases and to determine a more efficient treatment increasing adiponectin secretion or action. Furthermore, the search for diabesity genes in morbidly obese subjects is crucial to establish the genetic profile of this very high-risk population and for a better understanding of the molecular determinants of metabolic complications of obesity.…”

“…In mouse models of insulin resistance, recombinant adiponectin attenuates type 2 diabetes [4]. Adiponectin, in contrast to TNF-α and leptin, is decreased in subjects with increased fat mass [3], type 2 diabetes or CHD [5]. Prospective studies in Caucasians and in the diabetes-susceptible Pima Indian population, showed that subjects with high adiponectin levels were protected against type 2 diabetes (odds ratio [OR] 0.63 in Pima Indians) [6,7].…”

The role of total and high-molecular-weight complex of adiponectin in vascular function in offspring whose parents both had type 2 diabetes

“…Epidemiologically, serum levels of the protein correlate negatively with cardiac risk factors, positively with HDL-cholesterol and are lower in patients with coronary artery disease than in controls [13][14][15]. Adiponectin accumulates in rat carotid artery walls after balloon injury, but not in healthy vessel walls [16] and has been shown to suppress both the conversion of macrophages to foam cells and the migration of smooth muscle cells [6,17]. Adiponectin-deficient mice develop severe neointimal hyperplasia, that can be attenuated by adiponectin repletion [18] and the protein protects apo-E deficient mice from development of atherosclerosis [19].…”