cyclin-d1 and Liver-Failure

Transplanting donor livers with severe macrosteatosis is associated with increased risk of primary non-function (PNF). The purpose of this study was to identify steatosis-driven biomarkers as a predisposition to severe liver damage and delayed recovery following ischemia reperfusion injury. Wistar rats were fed a methionine- and choline-deficient (MCD) diet for up to three weeks to achieve severe macrosteatosis (>90%). Animals underwent diet withdrawal to control chow and/or underwent ischemia reperfusion and partial hepatectomy injury (I/R-PHx) and reperfused out to 7 days on control chow. For animals with severe macrosteatosis, hepatic levels of IL-33 decreased while Cyclin D1 levels increased in the absence of NF-κB p65 phosphorylation. Animals with high levels of nuclear Cyclin D1 prior to I/R-PHx either did not survive or had persistent macrosteatosis after 7 days on control chow. Survival 7 days after I/R-PHx fell to 57% which correlated with increased Cyclin D1 and decreased liver IL-33 levels. In the absence of I/R-PHx, withdrawing the MCD diet normalized IL-33, Cyclin D1 levels, and I/R-PHx survival back to baseline. In transplanted grafts with macrosteatosis, higher Cyclin D1 mRNA expression was observed. Shifts in Cyclin D1 and IL-33 expression may identify severely macrosteatotic livers with increased failure risk if subjected to I/R injury. Clinical validation of the panel in donor grafts with macrosteatosis revealed increased Cyclin D1 expression corresponding to delayed graft function. This pre-surgical biomarker panel may identify the subset of livers with increased susceptibility to PNF.

Topics: Adult; Animals; Biomarkers; Cyclin D1; Diet; Disease Models, Animal; Disease Susceptibility; Fatty Liver; Humans; Interleukin-33; Liver; Liver Failure; Liver Transplantation; Male; Middle Aged; Rats, Wistar; Reperfusion Injury; Survival Analysis

Adequate hepatocyte regeneration is mandatory for successful recovery after liver resection. The role of epidermal growth factor (EGF), by subcutaneous injection as a simple route, has not been clearly elucidated yet. Wistar rats underwent 70 or 90% hepatectomy, respectively, and were treated with EGF at day 2 and 3 or served as non-EGF-treated controls. Postoperatively, proliferative parameters (weight of liver remnants, number of mitotic and Ki-67 positive cells, expression of cyclin D1 protein) were evaluated. After 90% hepatectomy, 5 day survival was recorded following EGF treatment using different dosages. A significant increase of hepatocellular proliferation was observed after 70% hepatectomy. However, survival following 90% hepatectomy was not as positively affected, irrespective of EGF dosage, with most animals dead before EGF application was completed. Subcutaneous EGF injection can augment postoperative liver regeneration, however, it might be used only as a prophylactic and not as a therapeutic drug in case of liver insufficiency.

Topics: Analysis of Variance; Animals; Blotting, Western; Cell Proliferation; Cyclin D1; Epidermal Growth Factor; Hepatectomy; Immunohistochemistry; Injections, Subcutaneous; Ki-67 Antigen; Liver Failure; Liver Regeneration; Male; Models, Animal; Rats; Rats, Wistar; Survival Rate

The metabolic state effect of liver failure on liver gene regulation was evaluated in a rat model.. Following 70 or 90% hepatectomy and lipopolysaccharide or vehicle treatment at intervals up to 24 h, the liver remnants were analyzed for mRNA levels for acute-phase, liver-specific and growth-related proteins.. After 70% hepatectomy mRNA for alpha 1-acid glycoprotein, alpha 2-macroglobulin, thiostatin and fibrinogen, haptoglobin increased three- to sevenfold (P < 0.05), and mRNA for cyclin D and histone 3 increased seven- and 15-fold (P < 0.05), respectively. After lipopolysaccharide injection and 70% hepatectomy were done, mRNA for acute-phase proteins raised significantly (P < 0.05), more to five to 20-fold, while mRNA for growth-related proteins raised significantly (P < 0.05) less to three- to fourfold. After 90% hepatectomy, acute-phase protein mRNA increased five- to ninefold (P < 0.05) more than after 70% hepatectomy, while mRNA for histone 3 and cyclin D did not increase within 24 h, which indicates a delayed growth after 90% hepatectomy. In 90% of hepatectomized rats treated with lipopolysaccharide, acute-phase protein mRNA raised three- to sixfold (P < 0.05) less than after vehicle treatment.. In endotoxemia from liver failure, the synthesis of acute-phase proteins is upregulated by gene regulation at the expense of that for regeneration, which may be an appropriate response for immediate survival. In severe liver failure, endotoxin may interfere with the appropriate gene regulation.

Topics: Acute-Phase Proteins; alpha-Macroglobulins; Animals; Cyclin D1; Endotoxemia; Endotoxins; Fibrinogen; Gene Expression Regulation; Growth Substances; Haptoglobins; Hepatectomy; Kininogens; Liver Failure; Male; Orosomucoid; Rats; Rats, Wistar; RNA, Messenger; Up-Regulation

Liver regeneration stimulated by a loss of liver mass leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Mice with targeted disruption of the interleukin-6 (IL-6) gene had impaired liver regeneration characterized by liver necrosis and failure. There was a blunted DNA synthetic response in hepatocytes of these mice but not in nonparenchymal liver cells. Furthermore, there were discrete G1 phase (prereplicative stage in the cell cycle) abnormalities including absence of STAT3 (signal transducer and activator of transcription protein 3) activation and depressed AP-1, Myc, and cyclin D1 expression. Treatment of IL-6-deficient mice with a single preoperative dose of IL-6 returned STAT3 binding, gene expression, and hepatocyte proliferation to near normal and prevented liver damage, establishing that IL-6 is a critical component of the regenerative response.

Topics: Animals; Cyclin D1; Cyclins; DNA; DNA-Binding Proteins; G1 Phase; Gene Expression Regulation; Gene Targeting; Genes, Immediate-Early; Hepatectomy; Interleukin-6; Liver; Liver Failure; Liver Regeneration; Mice; Mice, Inbred C57BL; Mitosis; Mutation; Necrosis; Oncogene Proteins; Proto-Oncogene Proteins c-myc; STAT3 Transcription Factor; Trans-Activators; Transcription Factor AP-1