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

Abstract

Activation of LXR activity by synthetic agonists has been the focus of many drug discovery efforts with a focus on treatment of dyslipidemia and atherosclerosis. Many agonists have been developed, but all have been hindered due to their ability to efficaciously stimulate de novo lipogenesis. Here, we review the development of LXR inverse agonists that were originally optimized for their ability to enable recruitment of corepressors leading to silencing of genes that drive de novo lipogenesis. Such compounds have efficacy in animal models of MAFLD, dyslipidemia, and cancer. Several classes of LXR inverse agonists have been identified and one is now in clinical trials for treatment of severe dyslipidemia.

Characterization of an in vitro steatosis model simulating activated de novo lipogenesis in MAFLD patients

“…showed possible MAFLD treatment with new drug candidate TLC-2716. 42 TLC-2716 binds to LXR as an inverse agonist and showed reduced DNL and triglyceride (TG) absorption. JNK-IN-5A inhibit c-Jun N-terminal kinases (JNKs) activity that reduces phosphorylation to RXR-α.…”

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

“…SR9238 demonstrated the ability to reduce the basal transcriptional activity of LXR-α and LXR-β and to reduce the expression of genes involved in de novo lipogenesis. Moreover, it has liver-specific effects due to its rapid metabolism [ 82 ]. In animal models, SR9238 showed impressive results.…”

“…These inverse agonists have shown promising results in animal models, offering potential treatments for NASH, hypercholesterolemia, and cancer. Several LXR inverse agonist chemicals have been identified, with some progressing to clinical trials, expanding the therapeutic landscape for metabolic disorders [ 82 ]. NRs are involved in both the prevention and treatment of NAFLD.…”

Damaging mutations in LXRα uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver health

“…However, these eborts have been frustrated by challenges in dissociating the ebects of agonism on reverse cholesterol transport from the undesirable ebects on hepatic lipogenesis and by species-related ebects on lipoprotein metabolism [14,15]. Recently, interest has grown in adopting the converse approach: inhibiting hepatic LXR to suppress lipogenesis and hepatocyte triglyceride accumulation in the context of MASLD, a condition characterised by hepatic steatosis and cardiometabolic risk factors without significant alcohol consumption [20]. In a proportion of individuals, neutral lipid can be stored in the liver without significant hepatic inflammation.…”

“…It is therefore reasonable to ask whether suppression of lipogenesis via inverse agonism of LXR might be beneficial in MASLD. Indeed, treatment with LXR-inverse agonists reduce steatosis, inflammation and fibrosis in rodent models [20,26,27] and early-stage clinical trials of LXRinverse agonists for hypertriglyceridaemia and MASLD are in progress [28]. However, increased hepatic cholesterol has been observed in MASLD and is a putative risk factor for MASH [29][30][31].…”