Lu Jian, Shang Xuyang, Yao Bingyi, Sun Dongyi, Liu Jie, Zhang Yuanjin, Wang He, Shi Jingru, Chen Huaqing, Shi Tieliu, Liu Mingyao, Wang Xin
Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
Acta Pharm Sin B. 2023 Feb;13(2):648-661. doi: 10.1016/j.apsb.2022.08.005. Epub 2022 Aug 13.
Cholesterol is an important precursor of many endogenous molecules. Disruption of cholesterol homeostasis can cause many pathological changes, leading to liver and cardiovascular diseases. CYP1A is widely involved in cholesterol metabolic network, but its exact function has not been fully elucidated. Here, we aim to explore how CYP1A regulates cholesterol homeostasis. Our data showed that knockout (KO) rats presented cholesterol deposition in blood and liver. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were significantly increased in KO rats. Further studies found that the lipogenesis pathway (LXR-SREBP1-SCD1) of KO rats was activated, and the key protein of cholesterol ester hydrolysis (CES1) was inhibited. Importantly, lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterolemia models by inducing CYP1A. Our findings reveal the role of CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for the treatment of hypercholesterolemia.
胆固醇是许多内源性分子的重要前体。胆固醇稳态的破坏会导致许多病理变化，引发肝脏和心血管疾病。细胞色素P450 1A（CYP1A）广泛参与胆固醇代谢网络，但其确切功能尚未完全阐明。在此，我们旨在探究CYP1A如何调节胆固醇稳态。我们的数据表明，基因敲除（KO）大鼠出现血液和肝脏中的胆固醇沉积。KO大鼠的低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和总胆固醇的血清水平显著升高。进一步研究发现，KO大鼠的脂肪生成途径（肝X受体-固醇调节元件结合蛋白1-硬脂酰辅酶A去饱和酶1，LXR-SREBP1-SCD1）被激活，而胆固醇酯水解关键蛋白（CES1）受到抑制。重要的是，兰索拉唑可通过诱导CYP1A显著减轻高胆固醇血症模型大鼠的肝脏脂质沉积。我们的研究结果揭示了CYP1A作为胆固醇稳态潜在调节因子的作用，并为高胆固醇血症的治疗提供了新的视角。
