Chalcone derivative 1m mitigates hepatic fibrosis and inflammation, enhances cholesterol efflux and reduces atherosclerosis.

Atherosclerosis, which is characterized by lipid dysregulation, remains a major concern in cardiovascular medicine because of its multifactorial nature. Although lipid-lowering therapies, particularly statins, form the cornerstone of atherosclerosis management, issues such as statin intolerance and inadequate responses necessitate the exploration of novel therapeutic modalities. This study aimed to evaluate the hepatoprotective effects of 1m, a chalcone derivative and potential anti-atherosclerotic drug. In atherosclerosis-prone mouse models, the synthesized chalcone derivative 1m effectively reduced hepatic lipid accumulation and improved lipid profiles in high-cholesterol diet (HCD)-fed low-density lipoprotein receptor-knockout (Ldlr-/-) mice. Moreover, 1m promoted the expression of cholesterol regulatory genes, ATP-binding cassette transporters G5 (Abcg5), G8 (Abcg8), and cholesterol 7α-hydroxylase (Cyp7a1), in the liver, resulting in decreased hepatic triglyceride and cholesterol content, alongside increased hepatic bile acid and fecal cholesterol and bile acid contents in HCD-fed Ldlr-/- mice. RNA sequencing identified NR5A2 (liver receptor homolog-1, LRH-1) as a potential mediator of 1m-regulated gene expression, with increased expression observed in the liver of 1m-treated HCD-fed Ldlr-/- mice. In vitro studies using Huh7 hepatocytes revealed that 1m activates LRH-1, promoting its nuclear translocation and upregulating ABCG5, ABCG8, and CYP7A1 expressions, while the effects are attenuated by LRH-1 reverse agonist. Additionally, 1m reduced palmitic acid-induced apoptosis and significantly suppressed TGFβ-induced hepatic fibrosis and inflammation. Importantly, 1m ameliorated liver injury and atherosclerosis in HCD-fed Ldlr-/- mice. Our findings conclude the promising atheroprotective effects of 1m, facilitated by enhanced cholesterol efflux. Additionally, it confers hepatoprotective effects, thereby presenting a novel therapeutic avenue for atherosclerosis.