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Larsen 2021 Cell Mol Gastroenterol Hepatol

From Bioblast
Publications in the MiPMap
Larsen LE, van den Boogert MAW, Rios-Ocampo WA, Jansen JC, Conlon D, Chong PLE, Levels JHM, Eilers RE, Sachdev VV, Zelcer N, Raabe T, He M, Hand NJ, Drenth JPH, Rader DJ, Stroes ESG, Lefeber DJ, Jonker JW, Holleboom AG (2021) Defective lipid droplet - lysosome interaction causes fatty liver disease as evidenced by human mutations in TMEM199 and CCDC115. Cell Mol Gastroenterol Hepatol 13:583-97.

Β» PMID: 34626841 Open Access

Larsen LE, van den Boogert MAW, Rios-Ocampo WA, Jansen JC, Conlon D, Chong PLE, Levels JHM, Eilers RE, Sachdev VV, Zelcer N, Raabe T, He M, Hand NJ, Drenth JPH, Rader DJ, Stroes ESG, Lefeber DJ, Jonker JW, Holleboom AG (2021) Cell Mol Gastroenterol Hepatol

Abstract: Recently, novel inborn errors of metabolism were identified due to mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models and a mouse model.

Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very-low density lipoprotein (VLDL) range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and iPSC-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared to controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, or elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity.

Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. As this pathway remains understudied and its regulation largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.

Copyright Β© 2021 The Authors. Published by Elsevier Inc. All rights reserved.

β€’ Bioblast editor: Plangger M


Labels: MiParea: Respiration  Pathology: Other 

Organism: Human  Tissue;cell: Liver  Preparation: Intact cells 


Coupling state: OXPHOS, ET  Pathway: F, N  HRR: Oxygraph-2k 

2021-10