Fuchs_2012_Hepatology_56_270

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 beta-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 Tnfalpha 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.