Low-Expression Variant of Fatty Acid–Binding Protein 4 Favors Reduced Manifestations of Atherosclerotic Disease and Increased Plaque Stability

Abstract

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.)

Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity

“…Mice defi cient in aP2 or aP2 and the related protein FABP5/mal1 together have improved adipose and liver function, increased insulin sensitivity, and reduced fatty liver and cardiovascular disease in the context of high-fat diet and genetic mouse models of obesity and atherosclerosis ( 5-12 ). The link between aP2 and metabolic disease is also supported by genetic association studies in multiple populations demonstrating metabolic and cardiovascular benefi ts in individuals carrying a rare haploinsuffi ciency mutation in the aP2 locus, validating the relevance of this pathway in human disease ( 13,14 ). …”

Circulating FABP4 Is a Prognostic Biomarker in Patients With Acute Coronary Syndrome but Not in Asymptomatic Individuals

“…Its expression in atherosclerotic plaques of carotid arteries was previously found to predict cardiovascular outcome 7 or naturally occurring genetic lowexpression variant of FABP4 to promote plaque stability and to reduce the risk of cardiovascular events. 8 We therefore selected FABP4 for clinical validation as a circulating biomarker and considered 3 different situations, where a novel cardiovascular biomarker may improve clinical management of coronary artery disease (CAD). In clinical routine, electrocardiography and cardiac troponins are the gold standards for making the diagnosis of ACS.…”

Snapshots: Endoplasmic Reticulum Stress in Lipid Metabolism and Cardiovascular Disease

“…Moreover, high FABP4 expression in carotid plaques is associated with enhanced E R S , l i p i d a c c u m u l a t i o n , a n d i n c r e a s e d cardiovascular events (carotid atherosclerosis and stroke). This study suggests that low expression of FABP4 may contribute to reduced cardiovascular risk, probably by inhibiting ERS and reducing lipid accumulation (Saksi et al, 2014;Lv et al, 2017 (Qin et al, 2015). VLDLR promotes hypoxia-induced ERS in HL-1 cardiomyocytes and mouse heart tissue.…”

“…In a retrospective study, plaque stability was negatively correlated with ERS in carotid atherosclerosis patients (Saksi et al, 2014). Fibroblast growth factor 21 (FGF-21) treatment remarkably reduces the number and size of aortic plaques via the suppression of ERS, which attenuates aortic endothelium apoptosis and atherosclerosis in ApoE knockout mice .…”