Steatosis and Living Donor Liver Transplantation: Which Role for Cellular FLICE-inhibitory Protein, Death Ligands, and Fatty Acid Transporters
Final Report Abstract
So far, steatotic livers are not considered for transplantation, since impairment of liver function in steatohepatitis might account for primary non-function and living related donors with steatotic livers might face diminished recovery. Indeed, we found that obesity is associated with an increased risk for development of liver failure and several groups found impaired regeneration in steatohepatitis. However, recent data hint to a potential beneficial effect of lipid accumulation in liver regeneration and triglycerides might eventually be hepatoprotective in some models. We found that initiation of death receptor (DR) expression in hepatocytes, secondary to free fatty acid abundance, was associated with survival and proliferation, thus stimulating regeneration. Human primary hepatocytes exhibited elevated mRNA levels of TNFR1, CD95/Fas and the fatty acid transport protein (FATP) FABP1 after treatment with free fatty acids (FFA). Interestingly, the apoptosis rate (M30 Cytodeath ELISA) was not increased in FFA-treated hepatocytes. FFA incubation resulted in elevated mRNA levels of the anti-apoptotic molecule cFLIPL and in activation or fortified phosphorylation of ERK (extracellular signal regulated kinase). In a mouse model of western diet (WD) induced fatty liver disease, 70% hepatectomy was performed and apoptosis, regeneration, fat content as well as gene expression of DRs, FATPs and regenerative factors were analyzed. WD feeding caused a mild steatosis without inflammation including a significant increase of serum FFA and triglycerides in liver tissue as well as the up-regulation of DRs (TNFR1, CD95/Fas), FATPs (FATP5, FABP1, CD36), anti-apoptotic factors (bcl-2, bcl-xl, mcl-1) and hepatocyte growth factor (HGF). Surgical intervention enhanced serum FFA and triglyceride accumulation in liver tissue of standard diet (SD) fed animals as well as expression levels of DRs, FATPs, apoptosis- and regeneration-related molecules in WD- and SD-fed groups. This effect was more pronounced in WD-fed animals. Cell death (TUNEL staining) was slightly elevated after 70% hepatectomy in liver tissue, though no differences between SD- and WD-fed animals were observed. Cell proliferation was increased in liver tissue of WD-fed mice, characterized by significantly elevated amounts of Ki-67 positive cells. While steatohepatitis is associated with increased susceptibility to liver injury, mild steatosis might have positive effects on regeneration and may even facilitate proliferation after surgical interventions by activation of DRs and anti-apoptotic molecules.
Publications
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Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation. Hepatology 2010, 52: 1008-1016
Dechêne A, Sowa JP, Gieseler RK, Jochum C, Bechmann LP, El Fouly A, Schlattjan M, Saner F, Baba HA, Paul A, Dries V, Odenthal M, Gerken G, Friedman SL, Canbay A
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Apoptosis is associated with CD36/fatty acid translocase upregulation in non-alcoholic steatohepatitis. Liver Int 2010, 30: 850-859
Bechmann LP, Gieseler RK, Sowa JP, Kahraman A, Erhard J, Wedemeyer I, Emons B, Jochum C, Feldkamp T, Gerken G, Canbay A
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Apoptotic markers indicate nonalcoholic steatohepatitis in polycystic ovary syndrome. J Clin Endocrinol Metab 2010, 95: 343-348
Tan S, Bechmann LP, Benson S, Dietz T, Eichner S, Hahn S, Janssen OE, Lahner H, Gerken G, Mann K, Canbay A
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Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepatol 2010, 53: 639-647
Bechmann LP, Jochum C, Kocabayoglu P, Sowa JP, Kassalik M, Gieseler RK, Saner F, Paul A, Trautwein C, Gerken G, Canbay A
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Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology 2010, 51: 92-102
Kahraman A, Schlattjan M, Kocabayoglu P, Yildiz-Meziletoglu S, Schlensak M, Fingas CD, Wedemeyer I, Marquitan G, Gieseler RK, Baba HA, Gerken G, Canbay A
