Alcoholic liver disease(ALD)results from continuous and heavy alcohol consumption.The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention,which is a long proces...Alcoholic liver disease(ALD)results from continuous and heavy alcohol consumption.The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention,which is a long process with poor efficacy and low patient compliance.Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD,but CYP2E1 knockdown in humans was impractical,and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown.In this study,we developed a RNAi therapeutics delivered by lipid nanoparticle,and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks.This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers,and contributed to improved ALD symptoms in mice.The liver fat accumulation,hepatocyte inflammation,and fibrosis were reduced in ALD models.Therefore,this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.展开更多
基金This work is kindly supported by The National Key R&D Program of China:Chinese-Australian‘Belt and Road’Joint Laboratory on Traditional Chinese Medicine for the Prevention and Treatment of Severe Infectious Diseases(2020YFE0205100,China)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources(2060302,China)+7 种基金Zhenjiang social development project(SH2020036,China)National Key R&D Program of China(2019YFA0802801 and 2018YFA0801401,China)the National Natural Science Foundation of China(31871345 and 32071442,China)Medical Science Advancement Program(Basic Medical Sciences)of Wuhan University(TFJC2018004,China)the Fundamental Research Funds for the Central Universities(China)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-PT320-004,China)Applied Basic Frontier Program of Wuhan City(2020020601012216,China)Hubei Health Commission Young Investigator award(China)and startup funding from Wuhan University(China).
文摘Alcoholic liver disease(ALD)results from continuous and heavy alcohol consumption.The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention,which is a long process with poor efficacy and low patient compliance.Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD,but CYP2E1 knockdown in humans was impractical,and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown.In this study,we developed a RNAi therapeutics delivered by lipid nanoparticle,and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks.This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers,and contributed to improved ALD symptoms in mice.The liver fat accumulation,hepatocyte inflammation,and fibrosis were reduced in ALD models.Therefore,this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.
