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Liver-specific LXR inverse agonist restores lipid homeostasis in animal models and humans

ABSTRACT: Despite advances in lipid-lowering treatment, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality, underscoring the need for treatments that address residual risk. Targeting both the synthesis and clearance of triglyceride (TG)-rich lipoproteins is a promising approach. Liver X receptor (LXR) inhibition suppresses de novo lipogenesis and enhances clearance of TG-rich lipoproteins, but its clinical utility remains unexplored. Here, we demonstrate the pivotal role of LXR in lipid metabolism and metabolic diseases. In dysmetabolic animal models, LXR inverse agonists reduced plasma TG and cholesterol and improved insulin sensitivity by suppressing LXR activity and intestinal lipid absorption. Given concerns that systemic LXR inhibition may impair reverse cholesterol transport, we developed TLC-2716—an orally-administered, gut- and liver-restricted LXR inverse agonist. In human liver organoids modeling steatohepatitis, TLC-2716 reduced lipid accumulation and downregulated inflammation and fibrotic gene expression. In a Phase 1 clinical trial (NCT05483998), 14-day treatment with TLC-2716 was safe and resulted in placebo-adjusted reductions up to 38.5% in plasma TG and 60.8% in postprandial remnant cholesterol. These results highlight the safety and therapeutic potential of TLC-2716 as a novel treatment for managing dyslipidemia and reducing residual ASCVD risk.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299888 | GEO | 2025/11/14

REPOSITORIES: GEO

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Project description:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.

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Liver-specific LXR inverse agonist restores lipid homeostasis in animal models and humans

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