The function of ATP binding cassette protein A1(ABCA1)is central to cholesterol mobilization.Reduced ABCA1 expression or activity is implicated in Alzheimer’s disease(AD)and other disorders.Therapeutic approaches to ...The function of ATP binding cassette protein A1(ABCA1)is central to cholesterol mobilization.Reduced ABCA1 expression or activity is implicated in Alzheimer’s disease(AD)and other disorders.Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic.The risk factors for AD development and progression,including comorbid disorders such as type2 diabetes and cardiovascular disease,highlight the intersection of cholesterol transport and inflammation.Upregulation of ABCA1 can positively impact APOE lipidation,insulin sensitivity,peripheral vascular and blood-brain barrier integrity,and anti-inflammatory signaling.Various strategies towards ABCA1-boosting compounds have been described,with a bias toward nuclear hormone receptor(NHR)agonists.These agonists display beneficial preclinical effects;however,important side effects have limited development.In particular,ligands that bind liver X receptor(LXR),the primary NHR that controls ABCA1 expression,have shown positive effects in AD mouse models;however,lipogenesis and unwanted increases in triglyceride production are often observed.The longstanding approach,focusing on LXRβvs.LXRa selectivity,is over-simplistic and has failed.Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.展开更多
基金supported by NIH T32AG57468(USA)and American Heart Association 20PRE35150022(USA)and is a trainee in the University of Illinois Medical Scientist Training Program(USA)was provided through the UICentre for Drug Discovery as supported by the National Center for Advancing Translational Sciences,NIH UL1TR002003(USA)。
文摘The function of ATP binding cassette protein A1(ABCA1)is central to cholesterol mobilization.Reduced ABCA1 expression or activity is implicated in Alzheimer’s disease(AD)and other disorders.Therapeutic approaches to boost ABCA1 activity have yet to be translated successfully to the clinic.The risk factors for AD development and progression,including comorbid disorders such as type2 diabetes and cardiovascular disease,highlight the intersection of cholesterol transport and inflammation.Upregulation of ABCA1 can positively impact APOE lipidation,insulin sensitivity,peripheral vascular and blood-brain barrier integrity,and anti-inflammatory signaling.Various strategies towards ABCA1-boosting compounds have been described,with a bias toward nuclear hormone receptor(NHR)agonists.These agonists display beneficial preclinical effects;however,important side effects have limited development.In particular,ligands that bind liver X receptor(LXR),the primary NHR that controls ABCA1 expression,have shown positive effects in AD mouse models;however,lipogenesis and unwanted increases in triglyceride production are often observed.The longstanding approach,focusing on LXRβvs.LXRa selectivity,is over-simplistic and has failed.Novel approaches such as phenotypic screening may lead to small molecule NHR modulators that elevate ABCA1 function without inducing lipogenesis and are clinically translatable.
