title: Palmitate activation by fatty acid transport protein 4 as a model system for hepatocellular apoptosis and steatosis.
abstract: Fatty acid transport protein (FATP) 4 is a minor FATP in the liver but it has some activity towards palmitate 16:0 (Pal). We here chose FATP4 as a representative model enzyme for acyl-CoA synthetases (ACSs), and FATPs to determine whether Pal activation would lead to apoptosis and alteration in lipid metabolism. By using FATP4 overexpressed (FATP4) Huh-7 cells, we showed that FATP4 was localized in the endoplasmic reticulum (ER) and mitochondria of FATP4 cells. FATP4 cells were more responsive to Pal than the control GFP cells in increasing palmitoyl-CoA and oleoyl-CoA activities as well as apoptosis by ~2-3 folds. The lipoapoptosis susceptibility by FATP4 was coupled with the increased JNK, PUMA, caspase3, PARP-1 activation as well as Rac-1-mediated cytoskeletal reorganization, and decreased insulin sensitivity. This was associated with increased contents of neutral lipids and significant alteration in composition of phospholipids and sphingolipids including increased lysophosphatidylcholine (LPC), ceramide, and hexosylceramide, as well as an increase of saturated:polyunsaturated fatty acid ratio in LPC and PC, but a decrease of this ratio in phosphatidylethanolamine pool. By use of ceramide synthase inhibitors, our results showed that FATP4-sensitized lipoapoptosis was not mediated by ceramides. Moreover, FATP4 expression was increased in fatty livers in vivo. Thus, our model system has provided a clue that Pal activation FATP4 triggers hepatocellular apoptosis via altered phospholipid composition and steatosis by acylation into complex lipids. This may be a redundant mechanism for other ER-localizing ACSs and FATPs in the liver, and hence their involvement in the development of fatty liver disease.
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Disease, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Seeßle
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Disease, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.affiliation: Department of Internal Medicine IV, Gastroenterology and Infectious Disease, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: Walee.Chamulitrat@med.uni-heidelberg.de.
authors.forename: Walee
authors.initials: W
authors.lastname: Chamulitrat
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019308:Palmitic Acid / Q000378:metabolism*; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism; D014162:Transfection
chemical_list: D000214:Acyl Coenzyme A; D002518:Ceramides; C493410:FABP4 protein, human; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; D010743:Phospholipids; D013107:Sphingolipids; C017585:oleoyl-coenzyme A; D010171:Palmitoyl Coenzyme A; D019308:Palmitic Acid; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Fatty acid transport protein 4; Fatty acyl-CoA; Lipidomics; Lipoapoptosis; Saturated fatty acid; Steatosis