Jos Jansen

4 99 NAFLD Phenotype in Patients With V-ATPase Proton Pump Assembly Defects COPI can function on a phospholipid monolayer and buds of 60 nm nanoLDs. (66) These data suggest a non-canonical role for the GBF1-Arf1-COPI complex on the LD surface: by budding off of nano-lipid particles from the LD surface, this complex lowers surface tension and thereby supplies energy for membrane- bridge formation and subsequent translocation of LDAPs GPAT4, DGAT2, and brummer (fly homolog of ATGL) from the ER to LD (Figure 2).(60, 67) Absence of ATGL on LDs results in decreased lipolysis.(59) Again, dysfunction of COPI vesicles due to TMEM199 or CCDC115 deficiency can have a similar effect as knockdown of COPI and thus result in hepatic steatosis. Further research will be needed to see if this is a direct effect of TMEM199, CCDC115, and ATP6AP1 on COPI functioning, COPI vesicle trafficking or if this is an effect of attenuated non-canonical V-ATPase functioning. VLDL transport through COPII vesicles Very low-density lipoproteins (VLDLs) are synthesized in hepatocytes and responsible for export of TGs to other parts of the body. VLDL synthesis is dependent on the availability of TGs and microsomal triglyceride transfer protein (MTP).The importance of MTP in VLDL synthesis is highlighted by the development of hepatic steatosis in abetalipoproteinemia (MIM: 200100) patients due to a genetic defect in MTP .(68) LDAPs also play an important role as they transfer the triacylglycerols from the LD to the ER.(50) After correct assembly, VLDL particles are exported to the Golgi in a COPII-dependent manner. However, this is mediated by alternative COPII vesicles compared to routinely processed proteins.(69) Mutations in Sar1b, an assembly factor of COPII vesicles, result in chylomicron retention disease (MIM: 246700) with intracellular accumulation of chylomicrons.(70) There is limited data on events after fusion with Golgi membrane. For example, the issue regarding Golgi-located lipidation of VLDL particles has not been resolved yet.(71) Transport from the trans -Golgi network to the plasma membrane occurs via specialized vesicles.(72) However, comparable to intra-Golgi processing, this part of the secretory pathway has not been investigated to a level that allows to demonstrate the effects of disturbances in Golgi homeostasis. It is possible that defects in V-ATPase assembly factors impair COPII trafficking of VLDL particles resulting in hepatic steatosis. An alternative explanation is that intra Golgi trafficking of the lipidation machinery is impaired by defective Golgi trafficking resulting in diminished VLDL secretion and thus hepatic steatosis. More research is needed to elucidate this issue.