Polysome Profiling in Liver Identifies Dynamic Regulation of Endoplasmic Reticulum Translatome by Obesity and Fasting 英文参考文献.docVIP
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Polysome Profiling in Liver Identifies Dynamic Regulation of Endoplasmic Reticulum Translatome by Obesity and Fasting 英文参考文献
PolysomeProfilinginLiverIdentifiesDynamic
RegulationofEndoplasmicReticulumTranslatomeby
ObesityandFasting
SunengFu1,JasonFan1,JoshuaBlanco1,AlfredoGimenez-Cassina2,NikaN.Danial2,SteveM.Watkins1,
Go¨khanS.Hotamisligil1,3
*
1DepartmentofGeneticsandComplexDiseasesandDepartmentofNutrition,HarvardSchoolofPublicHealth,Boston,Massachusetts,UnitedStatesofAmerica,2Dana-
FarberCancerInstituteandHarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,3BroadInstituteofHarvardandMIT,Boston,Massachusetts,United
StatesofAmerica
Abstract
Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and
lipidmetabolism,whereasthestatusofproteinmetabolismisnotwellstudied.Here,weperformedcomparativepolysome
and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic
reticulum (ER)–associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We
discoveredthatERfromliversofobesemiceexhibitsageneralreductioninproteinsynthesis,andcomprehensiveanalysis
of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial
components,andbileacidmetabolismintheobesetranslatome.Nutrientavailabilityalsoplaysanimportantbutdistinct
roleinremodelingthehepaticERtranslatomeinleanandobesemice.Fastinginobesemicepartiallyreversedtheoverall
translatomicdifferencesbetweenleanandobesenonfastedcontrols,whereasfastingoftheleanmicemimickedmanyof
thetranslatomic changes induced by the development ofobesity. The strongest examples ofsuch regulationswere the
reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene
significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine
balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver
translato
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