An oral, liver-restricted LXR inverse agonist for dyslipidemia: preclinical development and phase 1 trial.

Targeting both the synthesis and clearance of triglyceride (TG)-rich lipoproteins is a promising approach.

同时针对富含甘油三酯（TG）的脂蛋白的合成和清除是一个有前景的方法。

Liver X receptor (LXR) repression can reduce plasma TG and cholesterol and improve insulin sensitivity by suppressing de novo lipogenesis and intestinal lipid absorption and enhancing clearance of TG-rich lipoproteins, but its clinical utility remains unexplored.

肝脏X受体（LXR）的抑制可以降低血浆甘油三酯和胆固醇，并通过抑制新生脂肪生成和肠道脂肪吸收以及增强富含甘油三酯的脂蛋白清除来改善胰岛素敏感性，但其临床效用尚未被探索。

Here we demonstrate the role of LXR inverse agonists in lipid metabolism and metabolic diseases in preclinical models and humans.

在这里，我们展示了LXR反向激动剂在临床前模型和人类脂质代谢和代谢性疾病中的作用。

Given concerns that systemic LXR repression may impair reverse cholesterol transport, we developed TLC-2716, an orally administered, gut- and liver-restricted LXR inverse agonist.

鉴于对全身性LXR抑制可能损害逆向胆固醇运输的担忧，我们开发了TLC-2716，这是一种口服给药、肠道和肝脏限制性的LXR反向激动剂。

In human liver organoids modeling steatohepatitis, TLC-2716 reduced lipid accumulation and suppressed inflammation and fibrotic gene expression.

在模拟脂肪性肝炎的人类肝器官中，TLC-2716减少了脂质积累并抑制了炎症和纤维化基因的表达。

In a randomized, placebo-controlledphase 1 clinical trial, 14-day treatment with TLC-2716 was well tolerated (primary endpoints) and resulted in placebo-adjusted reductions up to 38.5% in plasma TG and 61% in postprandial remnant cholesterol (secondary endpoints).

在一项随机、安慰剂对照的1期临床试验中，TLC-2716的14天治疗耐受性良好（主要终点），并且与安慰剂相比，血浆TG降低了高达38.5%，餐后残余胆固醇降低了61%（次要终点）。

In conclusion, these results highlight the tolerability and therapeutic potential of TLC-2716 as a treatment for managing dyslipidemia and reducing residual atherosclerotic cardiovascular disease risk in humans.

总之，这些结果强调了TLC-2716作为管理血脂异常和降低人类残余动脉粥样硬化心血管疾病风险的治疗潜力和耐受性。

ClinicalTrials.gov identifier: NCT05483998 .

ClinicalTrials.gov 注册号：NCT05483998 .