Apoptosis sensitization of hepatocytes by acyl-CoA synthetase 5 involves deregulation of sphingolipid metabolism and alterations in mitochondrial signalling

Fatty acid accumulation in hepatocytes and subsequent hepatocyte lipoapoptosis are key features in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and associated acute and chronic liver injury. The initial step in fatty acid and lipid metabolism is the activation of fatty acids catalyzed by long chain acyl-CoA synthetases (ACSL). ACSL5, a mitochondrially located isoform that is upregulated in hepatic steatosis has been revealed to increase hepatocellular apoptosis susceptibility. In this study, we investigated the molecular mechanisms selectively sensitizing hepatocytes to apoptosis by ACSL5. Using proteinchemical techniques as well as liquid chromatography, tandem mass spectrometry (LC-MS/MS), we demonstrate the involvement of hepatic sphingolipid metabolism and mitochondrial signaling in ACSL5-induced apoptosis sensitization. Sphingolipids play essential and diverse roles in many cellular pathways including proliferation and apoptosis. We show that high ACSL5 activity increased de novo synthesis of proapoptotic sphingolipids including ceramide and sphingosine, but decreased synthesis of antiapoptotic sphingolipids. Upregulation of mitochondrial sphingolipid levels was accompanied by structural modifications of mitochondria. Inhibition of Sphingolipid de novo synthesis significantly reduced apoptosis in ACSL5-overexpressing HepG2 cells. Furthermore, ACSL5 mediated activation of mitochondrial apoptosis signalling.These results indicate that deregulation of sphingolipid metabolism and mitochondrial signalling are distinct features of ACSL5-induced apoptosis sensitization. Furthermore, they stress the functional relevance of ACSL5 in promoting hepatocellular apoptosis as important mechanism in fatty liver-related disorders.

Literature:

Reinartz A, Ehling J, Leue A, Liedtke C, Schneider U, Kopitz J, Weis T, Hellerbrand C, Weiskirchen R, Knüchel R, Gassler N (2010) Lipid-induced up-regulation of human acyl-CoA synthetase 5 promotes hepatocellular apoptosis. Biochim Biophys Acta 1801, 1025 -1035Zheng W, Kollmeyer J, Symolon H, Momin A, Munter E, Wang E, Kelly S, Allegood JC, Liu Y, Peng Q, Ramaraju H, Sullards MC, Cabot M, Merrill AH, Jr. (2006) Ceramides and other bioactive sphingolipid backbones in health and disease: Lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochim Biophys Acta 1758, 1864 - 1884

NAFLD - apoptosis - acyl-CoA - sphingolipids