Lysosomal acid lipase (LAL)-dependent lipolysis degrades cholesteryl ester (CE) and triglyceride in the lysosome. LAL deficiency in human and mice leads to hypercholesterolemia, hepatic CE deposition, and atherosclerosis. Despite its hepatocyte-specific deficiency leads to CE accumulation, the regulation of LAL in cholesterol metabolic disease remains elusive. For the in vitro study, the target gene Lipa was transfected with recombinant shRNA or lentiviral vector in Hepa1-6 cells. It was found that LAL silencing in cells affected lysosomal function by reducing LAL activity and proteolytic activity, and altered the expression of genes related to cholesterol metabolism and autophagy, leading to cholesterol accumulation; whereas LAL overexpression improved the above effects. To explore the impacts of hepatic LAL on cholesterol metabolic disease in vivo, apolipoprotein E deficient (ApoE^−/−) mice were intravenously injected with lentivirus to achieve hepatic LAL overexpression and fed a Western diet for 16 weeks. The results showed that hepatic LAL overexpression significantly reduced plasma lipid levels, alleviated inflammation and oxidative status in plasma and liver, and attenuated hepatic steatosis and fibrosis in ApoE^−/− mice. Mechanically, hepatic LAL promoted cholesterol transport and biliary excretion by increasing liver X receptor alpha (LXRα) and its downstream genes, and modulated the compliance of the autophagy-lysosomal pathway. Our data provide the original evidence of the validity of hepatic LAL in controlling cholesterol metabolism and liver homeostasis, suggesting that targeting hepatic LAL may provide a promising approach to rescue cholesterol metabolic disorders, such as hypercholesterolemia and liver disease.

溶酶体酸性脂肪酶 (LAL) 依赖性脂解作用可降解溶酶体中的胆固醇酯 (CE) 和甘油三酯。人和小鼠的 LAL 缺乏会导致高胆固醇血症、肝 CE 沉积和动脉粥样硬化。尽管其肝细胞特异性缺陷导致 CE 积累，但 LAL 在胆固醇代谢疾病中的调节仍然难以捉摸。对于体外研究，目标基因Lipa用重组 shRNA 或慢病毒载体转染 Hepa1-6 细胞。发现细胞中LAL沉默通过降低LAL活性和蛋白水解活性影响溶酶体功能，改变胆固醇代谢和自噬相关基因的表达，导致胆固醇积累；而 LAL 过表达改善了上述效果。为了探讨肝 LAL 对体内胆固醇代谢疾病的影响，载脂蛋白 E 缺陷（ApoE ^-/-) 小鼠静脉注射慢病毒以实现肝脏 LAL 过表达并喂食西方饮食 16 周。结果表明，肝脏 LAL 过表达显着降低了血浆脂质水平，减轻了血浆和肝脏中的炎症和氧化状态，并减轻了ApoE 中的肝脏脂肪变性和纤维化^-/-老鼠。从机制上讲，肝脏 LAL 通过增加肝脏 X 受体α (LXRα) 及其下游基因来促进胆固醇转运和胆汁排泄，并调节自噬-溶酶体途径的顺应性。我们的数据提供了肝 LAL 在控制胆固醇代谢和肝脏稳态方面有效性的原始证据，表明靶向肝 LAL 可能提供一种有希望的方法来挽救胆固醇代谢紊乱，如高胆固醇血症和肝病。