Functional Study Of The HDAC6 Regulating Lipid Droplet Turnover In Adaptation To Nutrient Deprivation Via Selective Autophagy

Autophagy is conserved among the species,and has been evolved as an adaptive process in response to nutrient deprivation for the animal survival.Autophagy has three types: Macrophagy,Microphagy and Chaperone-mediated autophagy.By using the recognition adaptors,autophagy can selectively degrade various cellular cargos such as damaged mitochondrion,endoplasmic reticulum and misfolded protein aggregates,thus the autophagy could function to maintain the cell homeostasis and recover various cell raw materials for the development.Lipid droplet(LD)is a lipid storage organelle,and composed of a neutral lipid core consisting mainly of triacylglycerols(TAGs)and cholesteryl esters surrounded by a phospholipid monolayer.Although the exact mechanism of formation of lipid droplets is still unknown,it is proposed that they bud off the membrane of the endoplasmic reticulum and TAGs are collected between the two layers of its phospholipid membrane.The surface of lipid droplets is decorated by a number of proteins which play critical roles in the regulation of lipid metabolism.LDs could be turned over to release the fatty acid during starvation,then within divese pathways,these fatty acids are oxidized to provide energy for the tissues and organs.Recently,LD has been reported to be the cargo of starvation-induced autophagy,and could be degraded through Macrophagy in bulk.However,it is largely unknown how the autophagy machinery recognizes the LDs and whether autophagy can selectively degrade LDs.The liver is a vital organ in human,and it plays a crucial role in metabolism,regulation of glycogen storage,decomposition of red blood cells and hormone production.During starvation,the lipid mobilized from the adipose tissue accumulates largely in the liver,then the reaction of fat metabolism increases severly.Whereas,the lipidtoxin brought by the accumulated lipid will destroy the function of the hepatocyte.With the prevalent of NAFLD(Nonalcoholic fatty liver disease)all over the world,the process of the liver fat metabolism has attracted more and more focus of the researchers.Interestingly,the oenocytes of Drosophila known as hepatocyte-like cells also accumulate lipid mobilized from the fat body during the period of nutrient deprivation.In this study,we found that Drosophila histone deacetylase 6(dHDAC6),a key regulator of selective autophagy,is required for the LD turnover in the hepatic-like oenocytes in response to starvation.Moreover,we found that HDAC6 regulates LD turnover via p62/SQSTM1-mediated aggresome formation.The degradation of LDs would be surppressed in the condition of lacking HDAC6 and/or p62/SQSTM1.Moreover,HDAC6 lacking BUZ domain or p62/SQSTM1 without PB1 and/or LRS domain also makes the aggregate of HDAC6/p62 loss the function of LDs degradation.This finding identifies a new way of autophagic degradation of LD that requires selective autophagy machinery for the LD recognition and degradation.Our data also shows that loss of HDAC6 cause steatosis in response to starvation,which provide a potential link between selective autophagy and susceptible predisposition in stress conditions.