title: Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice.
abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by triglyceride (TG) accumulation and endoplasmic reticulum (ER) stress. Because fatty acids (FAs) may trigger ER stress, we hypothesized that the absence of adipose triglyceride lipase (ATGL/PNPLA2)-the main enzyme for intracellular lipolysis, releasing FAs, and closest homolog to adiponutrin (PNPLA3) recently implicated in the pathogenesis of NAFLD-protects against hepatic ER stress. Wild-type (WT) and ATGL knockout (KO) mice were challenged with tunicamycin (TM) to induce ER stress. Serum biochemistry, hepatic TG and FA profiles, liver histology, and gene expression for markers of hepatic lipid metabolism, ER stress, and inflammation were explored. Moreover, cell-culture experiments were performed in Hepa1.6 cells after the knockdown of ATGL before FA and TM treatment. TM increased hepatic TG accumulation in ATGL KO, but not in WT, mice. Lipogenesis and β-oxidation were repressed at the gene-expression level (sterol regulatory element-binding transcription factor 1c, fatty acid synthase, acetyl coenzyme A carboxylase 2, and carnitine palmitoyltransferase 1 alpha) in both WT and ATGL KO mice. Genes for very-low-density lipoprotein (VLDL) synthesis (microsomal triglyceride transfer protein and apolipoprotein B) were down-regulated by TM in WT and even more in ATGL KO mice, which displayed strongly reduced serum VLDL cholesterol levels. Notably, ER stress markers glucose-regulated protein, C/EBP homolog protein, spliced X-box-binding protein, endoplasmic-reticulum-localized DnaJ homolog 4, and inflammatory markers Tnfα and iNos were induced exclusively in TM-treated WT, but not ATGL KO, mice. Total hepatic FA profiling revealed a higher palmitic acid/oleic acid (PA/OA) ratio in WT mice, compared to ATGL KO mice, at baseline. Phosphoinositide-3-kinase inhibitor-known to be involved in FA-derived ER stress and blocked by OA-was increased in TM-treated WT mice only. In line with this, in vitro OA protected hepatocytes from TM-induced ER stress.
  
  
  CONCLUSIONS
  Lack of ATGL may protect from hepatic ER stress through alterations in FA composition. ATGL could constitute a new therapeutic strategy to target ER stress in NAFLD.
authors.affiliation: Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Fuchs
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.forename: Pooja
authors.initials: P
authors.lastname: Kumari
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Pollheimer
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stojakovic
authors.forename: Hubert
authors.initials: H
authors.lastname: Scharnagl
authors.forename: Emina
authors.initials: E
authors.lastname: Halilbasic
authors.forename: Judith
authors.initials: J
authors.lastname: Gumhold
authors.forename: Dagmar
authors.initials: D
authors.lastname: Silbert
authors.forename: Harald
authors.initials: H
authors.lastname: Koefeler
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D050155:Lipogenesis / Q000235:genetics / Q000502:physiology*; D008074:Lipoproteins; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D000217:Acyltransferases
chemical_list: D002784:Cholesterol; D008049:Lipase; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D014280:Triglycerides; D014415:Tunicamycin; C030104:lipoprotein cholesterol; C494794:PNPLA2 protein, human; D000217:Acyltransferases