High-Density Lipoprotein Extinguishes Fire in Fat

Abstract

Obesity is associated with a state of chronic, low-grade inflammation that reflects the accumulation of macrophages and other leukocytes in adipose tissue.1–3 In obesity cross-talk between adipocytes and macrophages amplifies the production of inflammatory cytokines and chemokines by macrophages and adipocytes,4 leading to local and systemic insulin resistance.5 Macrophage inflammation is also prominent in atherosclerosis, and cholesterol efflux pathways mediated by high-density lipoprotein (HDL), apolipoprotein AI (apoAI), and ATP-binding cassette transporters (ABC) act to suppress inflammation in macrophage foam cells.6 However, a possible role of cholesterol efflux pathways in the inflammation of obesity has not been previously addressed. In this issue of Circulation Research , Umemoto et al7 provide evidence that HDL and apoAI promote cholesterol efflux from adipocytes and reverse the expression of the proinflammatory chemotactic factors induced by saturated fatty acids in adipocytes, suggesting a novel mechanism for anti-inflammatory properties of HDL and the possibility that increasing HDL-mediated cholesterol efflux has beneficial effects on insulin resistance. Article, see p 1345 In previous work the authors of this study have demonstrated that saturated fatty acids such as palmitate stimulate monocyte chemotactic factor expression and production from 3T3-L1 adipocytes.8 This effect involves increased NADPH oxidase 4 (NOX4) activity, recruitment of NOX4 to lipid rafts, and enhanced reactive oxygen species (ROS) production.9 ROS generation has been implicated as an important contributor to insulin resistance in obesity and diabetes mellitus.10 HDL promotes cholesterol efflux and reduces cholesterol content in lipid rafts, altering the activity of signaling molecules in lipid rafts.11 Therefore, Umemoto et al7 investigated whether HDL-mediated cholesterol efflux from adipocytes affected chemotactic factor expression and whether this involved modulating NOX4 recruitment to lipid rafts and its activity. …