Background and Aims: The strategy to decrease atherosclerosis by stimulating liver X receptor (LXR) originated in mouse models. However, the first human trial testing an LXR agonist was prematurely terminated principally because of severe hyperlipidemia. We therefore investigated whether liver-humanized mice (LHM), i.e. mice repopulated with human hepatocytes, could serve as translatable human model to explain the negative outcomes of LXR agonism.

Methods: LHM were treated for 4 days with LXR agonist GW3965. Serum lipoproteins and lipids were separated by size-exclusion chromatography and quantified. Gene and protein expression was assessed by qPCR, Western blot or ELISA. Lipoprotein binding to human aortic proteoglycans (haPG) was assayed in vitro. Cholesterol precursors and composition, triglycerides and bile acid precursors in liver were assessed by GC-MS, colorimetry or LC-MS/MS.

Results: LXR stimulation in LHM increased cholesterol and triglycerides in VLDL and LDL, despite unaltered hepatic LDLR and circulating PCSK9 levels, and undetected CETP expression. haPG binding of lipoproteins was higher after GW3965 treatment, although their binding capacity was unchanged when correcting for serum cholesterol. In liver, LXR stimulation resulted in triglyceride and cholesteryl ester accumulation and reduced the precursors of bile acid and cholesterol biosynthesis. Down-regulation of CYP7A1 and of the SREBF2-system, and induction of SREBF1 variant c were observed.

Conclusions: Despite the lack of CETP, LHM displayed severe hyperlipidemia after LXR stimulation, subsequent to decrease in bile acid synthesis (leading to intrahepatic cholesterol accumulation) and increased triglyceride anabolism. These results endorse for the first time a mouse model recapitulating the molecular mechanisms of LXR agonism occurring in human liver.

02 - REDUCTION OF BILE ACID SYNTHESIS AND INTRAHEPATIC LIPID ACCUMULATION IN LIVER-HUMANIZED MICE DEFINE THE UNFAVORABLE PHARMACODYNAMICS OF LXR AGONISM IN HUMANS