Functions Of Cideb And ADRP In Regulating Liver VLDL Lipidation And Maturation And Lipid Homeostasis

Metabolic disorders including obesity, hyperlipidemia, insulin resistance,liver steatosis, and hypertension are a group of diseases associated withmetabolic malfunction and unbalanced energy homeostasis. Regulation of liverlipid metabolism is crucial in controlling lipid homeostasis and in thedevelopment of metabolic disorders. Lipid synthesized in liver should betransported into blood by very-low-density lipoproteins (VLDL) and utilized byperipheral tissues through circulation. Therefore, regulation of hepatic VLDLassembly, maturation and secretion is very important for liver lipid content andserum lipid level. VLDL assembly and maturation is a very complex processregulating by many factors including protein factors and lipid factors. Proteinfactors contain VLDL assembly-associated structural proteins,degradation-related chaperon proteins, vesicular trafficking factors, someenzymes and lipid droplet associated proteins. Bulk core lipid source for VLDLlipidation and the location where the lipidation occurs in are still unclear. Westudied on the lipid droplet proteins and the lipid factors.We found in our previous study that, Cideb, a member of celldeath-inducing DFF45-like effector (CIDE) family protein, could promoteVLDL lipidation and maturation through interaction with apolipoprotein B(apoB). However, the precise subcellular location of Cideb-mediated VLDLlipidation and factors modulating its activity remain elusive. We demonstratehere that Cideb is localized to the Golgi apparatus, ER and lipid droplet (LD). Itcan affect lipid content in Golgi and absence of Cideb decreases mature VLDLparticle number in Golgi dramatically. Cideb can also promote large LDformation. Interestingly, we observed that hepatic adiposedifferentiation–related protein (ADRP) levels are markedly increased in Cideb-/-mice. Liver-specific knockdown of ADRP in Cideb-/-mice resulted in a reducedhepatic triglycerides (TAG) accumulation, increased VLDL-TG secretion andthe accumulation of mature TAG-rich VLDL in the Golgi apparatus.Over-expression of ADRP showed the opposite effect. What’s more, ADRP could also regulate LD size. Knockdown of ADRP could increase hepatocyte LDsize. These data reveal that Cideb mainly plays its function in Golgi andpromotes VLDL lipidation and maturation in Golgi, while ADRP plays aninhibitory role in VLDL lipidation and maturation in Golgi and reduces lipidsecretion from liver. Cideb increases LD size and ADRP blocks large LDformation. Cideb and ADRP have opposite roles in regulating VLDL lipidation, LDsize and lipid homeostasis.We also suppose that LD directly provide the bulk lipids for VLDL lipidation.Cideb and ADRP may regulate LD size and VLDL lipidation and maturation throughcontrolling lipid transfer between LD and LD, or LD and VLDL.