Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists

Hyperlipidemia and increased circulating cholesterol levels are associated with increased cardiovascular disease risk.The liver X receptors (LXRs) are regulators ofde novolipogenesis and cholesterol transport and have been validated as potentialtherapeutic targets for the treatment of atherosclerosis. However, efforts to develop LXR agonists to reduce cardiovascular diseaseshave failed due to poor clinical outcomes-associated increased hepatic lipogenesis and elevated low-density lipoprotein (LDL)cholesterol (C). Here, we report that LXR inverse agonists are effective in lowering plasma LDL cholesterol and triglycerides inseveral models of hyperlipidemia, including theLdlrnull mouse model of atherosclerosis. Mechanistic studies demonstrate that LXRdirectly regulates the expression ofSoat2enzyme in the intestine, which is directly responsible for the re-uptake or excretion ofcirculating lipids. Oral administration of a gut-specific LXR inverse agonist leads to reduction ofSoat2expression in the intestine andeffectively lowers circulating LDL cholesterol and triglyceride levels without modulating LXR target genes in the periphery. Insummary, our studies highlight the therapeutic potential of the gut-restricted molecules to treat hyperlipidemia and atherosclerosisthrough the intestinal LXR-Soat2axis