•ResearchHighlights•

４　　　　 Vol．２６,No．３,２０１８　　SCIENCEFOUNDATIONINCHINA

AlossＧofＧfunctionmutationinLIMA１decreasesintestinalcholesterolabsorption

andpreventscardiovasculardisease

SupportedbytheNationalNaturalScienceFoundationofChina,acollaborativestudybythelaboratoriesofDr．SongBaoLiang(宋保亮)from WuhanUniversityandDr．MaYiTong (马依彤)fromtheFirstAffiliatedHospitalofXinjiang MedicalUniversitydemonstratesthatarareframeshiftmutationintheLIMA１genepromoteslowplasmalowＧdensitylipoproteincholesterol(LDLＧC)anddecreasesintestinal

Figure　LIMA１regulatesintestinalcholesterolabsorptionbyanchoringNPC１L１tomyosinVb．A;PedigreeoftheKazakhfamily withlowerlevelsofplasma LDLＧC;B,identification of the LIMA１ mutation in low LDLＧCmembers;C,SchematicmodelofNPC１L１ＧLIMA１ＧmyosinVbinteraction．

cholesterolabsorption．ThisworkwasrecentlypublishedinScience(２０１８,３６０(６３９３):１０８７—１０９２)．Cholesterolisanessentialcomponentofeukaryoticmembranesandtheprecursortomanybiological

activemolecules．Itcanbesynthesizeddenovoandobtainedfromthediet．However,toomuchlowＧdensitylipoproteinＧcholesterol(LDLＧC)intheplasmaisamajorriskfactorforcoronaryheartdiseaseandstroke．ThegeneticfactorsaffectingLDLＧChavenotbeenfullycharacterized．

TosearchforLDLＧCＧassociated mutations,theteamsledby Dr．Songand Dr．MaconductedacardiovascularrisksurveyinXinjiangUygurAutonomousRegionofChinaandfoundaChineseKazakhfamilywithinheritedlowlevelsofLDLＧCandreducedcholesterolabsorption．WholeＧexomesequencingandgenomeＧwidelinkageanalysisrevealedthattheLIMA１ＧK３０６fsvariantwasassociated withlowerplasmaLDLＧCofthisfamily．TheLIMA１gene(alsoknownasEPLINorSREBP３)hasnotbeenlinkedtolipidmetabolismpriortothestudy,andtheLIMA１ＧK３０６fsmutationhasnotbeenreportedinanypublisheddatabases．Inmice,LIMA１washighlyexpressedbythebrushbordermembraneofthesmallintestine．AblationofLIMA１inthesmallintestineimpaireddietarycholesterolabsorptionandameliorateddietＧinduced hypercholesterolemia． At themechanisticlevel,LIMA１interacted withNiemannＧPick C１Ｇlike １ (NPC１L１)andmyosinVb．NPC１L１isakeyproteinthatshuttlesbetweentheplasmamembrane(PM)andtheendocyticrecyclingcompartmenttomediateintestinalcholesterolabsorption,andthemolecularpathwayofNPC１L１Ｇdependentcholesteroluptake has been systematicallycharacterizedbyDr．Songandcolleaguesinthe past few years． The formation ofNPC１L１ＧLIMA１ＧMyosinVbternarycomplexregulatedNPC１L１transportationtothePMand consequently cholesterol absorptionthroughthesmallintestine．Thesefindingsrevealthecholesterolregulatory mechanisminhumansandsuggestthatpharmacologicaltargetingthroughtheLIMA１pathway mayserveasanewstrategytotreathypercholesＧterolemia．