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 significantly 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 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.

New insights of CYP1A in endogenous metabolism: a focus on single nucleotide polymorphisms and diseases

Cytochrome P4501A(CYP1A),one of the major CYP subfamily in humans,not only metabolizes xenobiotics including clinical drugs and pollutants in the environment,but also mediates the bio transformation of important endogenous substances.In particular,some single nucleotide polymorphisms(SNPs)for CYPIA genes may affect the metabolic ability of endogenous substances,leading to some physiological or pathological changes in humans.This review first summarizes the metabolism of endogenous substances by CYPIA,and then introduces the research progress of CYPIA SNPs,especially the research related to human diseases.Finally,the relationship between SNPs and diseases is discussed.In addition,potential animal models for CYPIA gene editing are summarized.In conclusion,CYP1A plays an important role in maintaining the health in the body.

Characterization of organic anion transporting polypeptide 1b2 knockout rats generated by CRISPR/Cas9:a novel model for drug transport and hyperbilirubinemia disease

Organic anion transporting polypeptide 1 B1 and 1 B3(OATP1 B1/3)as important uptake transporters play a fundamental role in the transportation of exogenous drugs and endogenous substances into cells.Rat OATP1 B2,encoded by the Slcolb2 gene,is homologous to human OATP1 B1/3.Although OATP1 B1/3 is very important,few animal models can be used to study its properties.In this report,we successfully constructed the Slco1 b2 knockout(KO)rat model via using the CRISPR/Cas9 technology for the first time.The novel rat model showed the absence of OATP1 B2 protein expression,with no offtarget effects as well as compensatory regulation of other transporters.Further pharmacokinetic study of pitavastatin,a typical substrate of OATP1 B2,confirmed the OATP1 B2 function was absent.Since bilirubin and bile acids are the substrates of OATP1 B2,the contents of total bilirubin,direct bilirubin,indirect bilirubin,and total bile acids in serum are significantly higher in Slco1 b2 KO rats than the data of wild-type rats.These results are consistent with the symptoms caused by the absence of OATP1 B1/3 in Rotor syndrome.Therefore,this rat model is not only a powerful tool for the study of OATP1 B2-mediated drug transportation,but also a good disease model to study hyperbilirubinemia-related diseases.