Abstract
It has been increasingly recognized that inflammation plays an important role in the pathogenesis of cardiovascular disease (CVD). In obesity, adipose tissue inflammation, especially in the visceral fat depots, contributes to systemic inflammation and promotes the development of atherosclerosis. Adipocyte fatty acid-binding protein (AFABP), a lipid chaperone abundantly secreted from the adipocytes and macrophages, is one of the key players mediating this adipose-vascular cross-talk, in part via its interaction with c-Jun NH2-terminal kinase (JNK) and activator protein-1 (AP-1) to form a positive feedback loop, and perpetuate inflammatory responses. In mice, selective JNK inactivation in the adipose tissue significantly reduced the expression of AFABP in their adipose tissue, as well as circulating AFABP levels. Importantly, fat transplant experiments showed that adipose-specific JNK inactivation in the visceral fat was sufficient to protect mice with apoE deficiency from atherosclerosis, with the beneficial effects attenuated by the continuous infusion of recombinant AFABP, supporting the role of AFABP as the link between visceral fat inflammation and atherosclerosis. In humans, raised circulating AFABP levels are associated with incident metabolic syndrome, type 2 diabetes and CVD, as well as non-alcoholic steatohepatitis, diabetic nephropathy and adverse renal outcomes, all being conditions closely related to inflammation and enhanced CV mortality. Collectively, these clinical data have provided support to AFABP as an important adipokine linking obesity, inflammation and CVD. This review will discuss recent findings on the role of AFABP in CVD and mortality, the possible underlying mechanisms, and pharmacological inhibition of AFABP as a potential strategy to combat CVD.
Highlights
In a Mendelian randomization (MR) study involving more than 360,000 participants from the UK Biobank, each genetically instrumented increase in body mass index (BMI) of 1 kg/m2 was associated with a significantly higher risk of most cardiovascular outcomes including hypertension, atrial fibrillation, coronary heart disease (CHD), heart failure and peripheral vascular disease (PVD) [10]
Bone marrow transplant experiments revealed that macrophage-specific Adipocyte fatty acid-binding protein (AFABP) deficiency reduced atherosclerotic lesions in mice with apolipoprotein E (ApoE) deficiency, to a similar extent as those with whole body AFABP deficiency, suggesting that much of the pro-atherogenic effects of AFABP are specific to its actions in macrophages [28]
Adipose tissue inflammation with dysregulated adipokine secretion is crucial to the pathogenesis of adverse cardiovascular outcomes in obesity
Summary
In a pooled analysis of 19.2 million participants, the age-standardized prevalence of obesity has tripled in men and doubled in women over the last four decades. If these trends continue, around 1 in 5 of the global population will become obese by year 2025 [2]. Predicted fat mass index was associated with an even broader list of cardiovascular outcomes including ischemic stroke These findings corroborated with another large MR study which demonstrated the causal effects of adiposity on CVD [11]. This review will focus on adipocyte fatty acid-binding protein (AFABP) and present the recent data on its role as an important adipokine linking obesity, inflammation and CVD
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