Article first published online: 29 MAY 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 1, pages 270–280, July 2012
How to Cite
Fuchs, C. D., Claudel, T., Kumari, P., Haemmerle, G., Pollheimer, M. J., Stojakovic, T., Scharnagl, H., Halilbasic, E., Gumhold, J., Silbert, D., Koefeler, H. and Trauner, M. (2012), Absence of adipose triglyceride lipase protects from hepatic endoplasmic reticulum stress in mice. Hepatology, 56: 270–280. doi: 10.1002/hep.25601
Potential conflict of interest: Nothing to report.
This work was supported by grant F3008-B05 from the Austrian Science Foundation and European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement HEALTH-F2-2009-241762 for the project FLIP (to M.T.).
- Issue published online: 3 JUL 2012
- Article first published online: 29 MAY 2012
- Accepted manuscript online: 23 JAN 2012 06:11AM EST
- Manuscript Accepted: 29 DEC 2011
- Manuscript Received: 9 SEP 2011
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. (HEPATOLOGY 2012;56:270–280 )