Abstract 1099: Adiponectin Enhances De Novo Hepatic HDL Synthesis Through LXR Alpha-and COUP-TFII-Dependent Pathways
Background: HDL and apolipoprotein A-I (ApoA-I) take up cholesterol from peripheral tissues and transport it back to the liver, a system called “reverse cholesterol transport (RCT)”. Both ApoA-I and ATP-binding cassette transporter A1 (ABCA1) are the rate-limiting factors that generate HDL in the liver. We for the first time identified adiponectin (APN) from adipocytes and have reported that it inhibits the development of atherosclerosis. We found a positive correlation between plasma HDL-C and APN concentrations in humans, and plasma APN is decreased in patients with coronary artery disease (CAD) and metabolic syndrome. We have shown that APN accelerates RCT by increasing the hepatic expression of ApoA-I and ABCA1. In the current study, we further evaluated the molecular mechanism of APN-induced enhancement of ApoA-I and ABCA1expression by testing whether COUP-TFII, one of the orphan receptors, and LXR alpha are involved in this mechanism.
Methods: A human hepatoma cell line, HepG2 cells, were incubated for 20 h in the culture medium containing recombinant human APN after the incubation for 12 h with siRNA or control RNA for COUP-TFII or LXR alpha and the mRNA levels of ApoA-I and ABCA1 were measured by real time PCR.
Results: APN up-regulated the mRNA and protein levels of ApoA-I and ABCA1 in HepG2 cells. Furthermore, the expressions of COUP-TFII and LXR alpha were also significantly increased by APN, while these expression levels were significantly lower in APN-knockout compared with wild-type mice. In HepG2 cells, the reduction of COUP-TFII by siRNA reduced the APN-induced enhancement of ApoA-I but not ABCA1. The siRNA-mediated inhibtion of LXR alpha attenuated the influence of APN on ABCA1 expression.
Conclusions: APN might protect against atherosclerosis by enhancing de novo hepatic HDL synthesis through both COUP-TFII- and LXR alpha-dependent pathways.