Jos Jansen

4 101 NAFLD Phenotype in Patients With V-ATPase Proton Pump Assembly Defects ◄ Figure 2. COPI vesicles in NAFLD pathogenesis and V-ATPase assembly factors The left pane depicts current model of COPI and hepatic lipid processing. 1. COPI is involved in budding of of nano lipid droplets (LD). Arf1 acts as an initiator of COPI assembly and is activated by GBF1-GEF via replacement of GDP by GTP an deactivated by ELMOD2-GAP. As a result of nano-LD formation lipid droplet surface tension is lowered resulting in 2. The formation of membrane bridges and relocation of LD associated proteins to the LD for lipolysis. The right pane shows the V0 domain of the V-ATPase is assembled in the ER membrane. TMEM199 and CCDC115 stabilize subunit a. Ac45 and VMA21 stabilize the proteolipid ring. These four V-ATPase assembly factors then transport the VO domain to the cis-Golgi via COPII vesicles. Retrograde transport of VMA21 (and possibly TMEM199 and CCDC115) is mediated by COPI coated vesicles. Our model is that V-ATPase assembly factor deficiencies result in defective retrograde Golgi transport by inhibiting COPI or COPII function or by affecting one of its regulators Arf1, GBF1, or ELMOD2. When COPI function is hampered nano- LD formation is not initiated ultimately resulting in decreased lipolysis and increased hepatic cellular triglycerides levels. Conclusion The V-ATPase assembly factor deficiencies are a new group of inborn errors of metabolism that have to be considered in the differential diagnosis of secondary NAFLD. The hepatic phenotype ranges from mild impairment to end-stage liver disease necessitating liver transplantation. We propose a multifaceted etiology based on abnormal Golgi apparatus homeostasis. This can lead to defective COPI and COPII vesicle-mediated protein and lipid trafficking in combination with abnormal glycosylation. Screening can easily be done via glycoanalytical techniques. Better awareness of these genetic defects will improve patient outcome and provide new insights in the etiology of NAFLD. Author’s contributions JCJ, DWdrafted themanuscript, tables and figures, MvS reviewed themanuscript, VR, JPHD and DL designed and reviewed the manuscript. MvS received funding from the Netherlands Organisation for Scientific Research (VENI grant 016168079). VR serves as a Scientific Advisor of Phenex Pharmaceuticals AG, Galmed Pharmaceuticals Ltd., Genfit SA and Tobira Therapeutics, Inc. JPHD has served on advisory boards of AbbVie, Gilead, Intercept. His Department receives research funding from Falk, Abbvie, Ipsen, and Novartis. All reimbursements go to the Radboudumc.