Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists

Abstract

Hyperlipidemia and increased circulating cholesterol levels are associated with increased cardiovascular disease risk. The liver X receptors (LXRs) are regulators of de novo lipogenesis and cholesterol transport and have been validated as potential therapeutic targets for the treatment of atherosclerosis. However, efforts to develop LXR agonists to reduce cardiovascular diseases have 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 in several models of hyperlipidemia, including the Ldlr null mouse model of atherosclerosis. Mechanistic studies demonstrate that LXR directly regulates the expression of Soat2 enzyme in the intestine, which is directly responsible for the re-uptake or excretion of circulating lipids. Oral administration of a gut-specific LXR inverse agonist leads to reduction of Soat2 expression in the intestine and effectively lowers circulating LDL cholesterol and triglyceride levels without modulating LXR target genes in the periphery. In summary, our studies highlight the therapeutic potential of the gut-restricted molecules to treat hyperlipidemia and atherosclerosis through the intestinal LXR-Soat2 axis.

Trust Your Gut: Strategies and Tactics for Intestinally Restricted Drugs

“…The unexpected observation that both 18 and 19 reduced the levels of low-density lipoprotein (LDL) cholesterol in plasma led to the hypothesis that this effect was driven by LXR in the intestine and/or liver. In a more recent study, the same group showed that, when dosed orally, compound 19 significantly suppresses the expression of intestinal sterol O -acyltransferase 2 (SOAT2), an LXR target gene that plays a key role in intestinal cholesterol reabsorption . Importantly, the resulting reduction in plasma LDL cholesterol and triglyceride levels takes place without modulating LXR target genes in the periphery.…”

Development of LXR inverse agonists to treat MAFLD, NASH, and other metabolic diseases

“…When examining the expression of intestinal genes that changed with SR9238 or SR9243 treatment (i.p.) we found that sterol O-acyltransferase 2 ( Soat2 ) gene expression was suppressed by ∼95% ( 86 ). This intrigued us given that SOAT2 has been a target for development of drugs to treat hypercholesterolemia and atherosclerosis ( 87 ).…”

“…Mice with an intestine specific KO of Soat2 are resistant to development of elevated plasma LDL-C on a high cholesterol diet ( 89 ) suggesting that targeting intestinal SOAT2 function or expression may be sufficient to provide this benefit. With our knowledge that SR9243 had no significant oral bioavailability we treated Ldlr null mice on a high cholesterol diet and observed that even though there was no liver or plasma exposure when SR9243 was administered orally, LDL-C was substantially decreased and was associated with repression of intestinal Soat2 expression and increased fecal cholesterol elimination ( 86 ). These data provided us with a clear mechanism that was driving the reduction in plasma LDL-C that we consistently observed as well as suggested that such compounds may hold utility in treatment of hypercholesterolemia, particularly in individuals that have mutations in the LDL receptor driving familial hypercholesterolemia.…”

Future therapeutic perspectives in nonalcoholic fatty liver disease: a focus on nuclear receptors, a promising therapeutic target

“…Furthermore, in the context of chronic ethanol-induced liver disease, SR9238 attenuated fat accumulation, inflammation, and fibrosis [ 83 ]. Furthermore, SR9238 revealed an interesting reduction in LDL-C levels by suppressing the expression of sterol O-acyltransferase 2 (Soat2), suggesting its potential for treating hypercholesterolemia [ 84 , 85 ].…”