Background-Fatty acid-binding protein 4 (FABP4 or aP2 in mice) has been identified as a key regulator of core aspects of cardiometabolic disorders, including lipotoxic endoplasmic reticulum stress in macrophages. A functional promoter polymorphism (rs77878271) of human FABP4 gene has been described resulting in reduced FABP4 transcription. Methods and Results-We investigated the effects of this low-expression variant of FABP4 on cardiovascular morbidity and carotid atherosclerosis on a population level (n=7491) and in patient cohorts representing endarterectomized patients with advanced carotid atherosclerosis (n=92) and myocardial infarction (n=3432). We found that the low-expression variant was associated with decreased total cholesterol levels (P=0.006) with the largest reduction in variant allele homozygotes. Obese variant allele carriers also showed reduced carotid intima-media thickness (P=0.010) and lower prevalence of carotid plaques (P=0.060). Consistently, the variant allele homozygotes showed 8-fold lower odds for myocardial infarction (P=0.019; odds ratio, 0.12; 95% confidence interval, 0.003-0.801). Within the carotid plaques, the variant allele was associated with a 3.8-fold reduction in FABP4 transcription (P=0.049) and 2.7-fold reduction in apoptosis (activated caspase 3; P=0.043). Furthermore, the variant allele was enriched to patients with asymptomatic carotid stenosis (P=0.038). High FABP4 expression in the carotid plaques was associated with lipid accumulation, intraplaque hemorrhages, plaque ulcerations, and phosphoactivated endoplasmic reticulum stress markers. Conclusions-Our results reveal FABP4 rs77878271 as a novel variant affecting serum total cholesterol levels and cardiovascular risk. A therapeutic regimen reducing FABP4 expression within the atherosclerotic plaque may promote lesion stability through modulation of endoplasmic reticulum stress signaling, and attenuation of apoptosis, lipid burden, and inflammation. (Circ Cardiovasc Genet. 2014;7:588-598.)

Background and Purpose-Adipophilin is an adipose differentiation-related protein expressed in lipid-containing cells.Using DNA microarray analysis, we previously found the adipophilin gene (ADFP) to be overexpressed in symptomatic carotid plaques (CP

Background-CD36 is a macrophage scavenger receptor mediating the uptake of modified lipoproteins, whereas the ABCA1 transporter counteracts this effect by mediating cellular lipid efflux. Based on a DNA microarray, we previously found that the CD36 and ABCA1 genes were overexpressed in symptom-causing carotid plaques (CP) compared with nonsymptomcausing CP. To evaluate their role in CP destabilization, we conducted detailed immunohistochemical studies on the localization of lipids, CD36 and ABCA1 proteins, extravasated red blood cells, and atheromatous/necrotic tissue. Methods-Ninety-two high-grade (Ͼ70%) stenosing CP obtained from carotid endarterectomy were Oil-red-O-stained for evaluation of neutral lipids. Subgroups of nonsymptom-causing and symptom-causing CP (nϭ42) were further analyzed by immunostaining adjacent histological sections against CD36 and ABCA1 and examining them microscopically. Results-When compared with nonsymptom-causing CP, the amount of extracellular lipid and the expression of CD36 protein were elevated in symptom-causing CP, but no difference was found in ABCA1 expression. These observations were also confirmed when ulcerated and nonulcerated CP were compared. In ulcerated CP, CD36 protein expression was higher than that of ABCA1, and the opposite was true in nonulcerated CP. CD36 colocalized with extravasated red blood cells and atheromatous or necrotic areas in the various types of CP. A dvanced atherosclerotic plaques in the internal carotid artery wall are considered as a clinical threat potentially leading to stroke. A spectrum of factors underlying the final destabilization and rupture of the plaques has been studied, but distinguishing between high-risk and low-risk plaques is still an enigma. However, one of the morphological features of high-risk plaques seems to be a vast lipid-filled core, the formation of which is fueled by the death of engorged lipid-filled macrophage foam cells. Conclusions-OurIn a genome-wide microarray expression study of advanced carotid plaques (CP), we discovered that the transformation of a CP from nonsymptom-causing to symptomcausing coincided with increased expression of macrophage adipophilin, 4 a lipid-loading marker. We also found that CD36 and ABCA1 genes were overexpressed in symptomcausing CP, and the result was replicated by real-time reverse-transcription polymerase chain reaction for CD36 (Saksi et al, unpublished data, 2009). Interestingly, both CD36 and ABCA1 seem to play an important role in balancing macrophage lipid intake and efflux. Oxidized low-density lipoprotein-scavenging CD36, a multifunctional membrane glycoprotein, is considered essential for foam cell formation, 1 and its expression is further stimulated by its own ligand. 2 This vicious cycle potentially leading to fatal cholesterol overload is partly inhibited by ABCA1, a membrane transporter protein of ATP-binding cassette (ABC) family, widely supported in its atheroprotectiveness, removing free cholesterol and phospholipids, and necessary for the initiation of macrophag...