Abstract 61: LXR Agonist Treatment of Nonhuman Primates Increases LDL Cholesterol due to Decreased Hepatic LDL Receptor Expression
Reverse cholesterol transport (RCT) is a process whereby cholesterol from foam cells in atherosclerotic plaques is removed by HDL, transported to the liver, secreted into bile, and excreted in the feces. Treatment of mice with LXR agonist can significantly increase RCT and inhibit atherosclerosis. Therefore, it would be anticipated that LXR agonists would also increase RCT and be anti-atherogenic in humans. However, cynomolgus monkeys treated with the LXR agonist GW3965 had significant increases in LDLc, which could be due to elevated hepatic expression of the inducible degrader of the LDL receptor (IDOL). IDOL is an E3 ubiquitin ligase that promotes the ubiquitination of the LDL receptor (LDLR) on its cytoplasmic domain, thereby targeting it for degradation. We recently discovered that GW3965 treatment of mice caused an ~3-fold increase in IDOL expression in the small intestine and consequently increased the turnover of the LDLR. In livers of GW3965 treated mice, LDLR protein was unchanged and IDOL expression was only increased by ~20%. However, treatment of human hepatoma cells with GW3965 increased IDOL 7-fold resulting in very low levels of LDLR protein expression. Therefore, we hypothesized that in humans and nonhuman primates, LXR agonist treatment would increase LDLc by inducing IDOL-dependent degradation of hepatic LDLR. After treating cynomolgus monkeys with GW3965 for 7 days, we found that HDLc was increased by ~20% while LDLc was increased by ~100%. The increase in LDLc was accompanied by a dramatic increase in plasma apoB100 and apoE concentration and a significant decrease in hepatic LDLR protein. We are currently determining the potential role of hepatic IDOL expression on these effects. We also found that unlike mice, monkeys treated with GW3965 did not display an increase in hepatic lipids, biliary cholesterol, and fecal neutral sterol excretion. These findings show that LXR activation has very different effects on lipoprotein metabolism and RCT in monkeys compared to mice. Our data suggest that LXR agonists are likely to exert both pro- and anti-atherosclerotic effects in primates and that these complex effects must be considered in the development of LXR agonists as drugs.
- © 2013 by American Heart Association, Inc.