New insights into the mechanism of low high-density lipoprotein cholesterol in obesity

Abstract

Obesity, a significant risk factor for various chronic diseases, is universally related to dyslipidemia mainly represented by decreasing high-density lipoprotein cholesterol (HDL-C), which plays an indispensible role in development of cardiovascular disease (CVD). However, the mechanisms underlying obesity and low HDL-C have not been fully elucidated. Previous studies have focused on the alteration of HDL catabolism in circulation following elevated triglyceride (TG). But recent findings suggested that liver and fat tissue played pivotal role in obesity related low HDL-C. Some new molecular pathways like microRNA have also been proposed in the regulation of HDL metabolism in obesity. This article will review recent advances in understanding of the potential mechanism of low HDL-C in obesity.

Figure 1

Effect of adipocyte on HDL. Hypertrophied adipocytes manifest several altered metabolic properties that play a role in lowered HDL-C. Adipocyte inflammation impairs its cholesterol efflux to HDL while cholesterol influx to adipocyte is increased in the state of obesity. In addition, altered adipokines downregulate apoA-I and ABCA1 gene expression in hepatocytes, thus reduce HDL assembly in the liver. ABCA1, ATP-binding cassette transporter A1; SR-BI, scavenger receptor type-BI; APN, adiponectin; TNF-a, tumor necrosis factor-α; IL-1β, interleukin-β; ATMc, adipose tissue macrophage content; apoA-I, apolipoprotein AI; HDL-C, high-density lipoprotein cholesterol.

Figure 2

Hepatic miR-33 and its host gene coordinate HDL-C and TG variations in obesity. In the state of obesity, hyperinsulinemia and disorders of adipokines would induce the expression of hepatic SREBP-1c gene as well as miR-33b. The upregulation of SREBP-1c would active its downstream genes and accelerate TG synthesis; upregulation of miR-33b would repress hepatic HDL assembly through the inhibition of ABCA1 and promote fat accumulation through the repression of fatty acid degradation. APN, adiponectin; TNF-a, tumor necrosis factor-α; srebf-1c, sterol regulatory element-binding transcription factor; miR-33b, microRNA-33b; FAS, fatty acid synthetase; ACC, acetyl-CoA carboxylase; CPT1A, carnitine palmitoyltransferase 1A; CROT, carnitine O-octanoyltransferase; HADHB, β-subunit of the mitochondrial trifunctional protein; ABCA1, ATP-binding cassette transporter A1; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride.