The role of CYP1A1/2 in cholesterol ester accumulation provides a new perspective for the treatment of hypercholesterolemia

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 CYP1A1/2 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 signif-icantly increased in KO rats. Further studies found that the lipogenesis pathway (LXRa-SREBP1-SCD1) of KO rats was activated, and the key protein of cholesterol ester hydrolysis (CES1) was inhib-ited. Importantly, lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterole-mia 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.(c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Cholesterol is a precursor for various endogenous molecules and its disruption can lead to liver and cardiovascular diseases. The function of CYP1A in cholesterol homeostasis has not been fully understood. This study aims to explore the role of CYP1A in regulating cholesterol homeostasis. The results show that CYP1A1/2 knockout rats exhibit cholesterol deposition in blood and liver, with increased levels of LDL cholesterol, HDL cholesterol, and total cholesterol. The lipogenesis pathway is activated, while the protein CES1 is inhibited in these rats. Lansoprazole can alleviate hepatic lipid deposition in hypercholesterolemia models by inducing CYP1A. These findings suggest CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for hypercholesterolemia treatment.