Kupfferzell-abhängige Regulation der Leberregeneration nach partieller Hepatektomie

Diese Arbeit präsentiert umfassende Daten zur hepatischen Architektur, Mikrozirkulation und zellulären Integrität während des Regenerationsprozesses nach 70%iger Leberresektion. Wir konnten zeigen, dass die Stimulation der hepatozellulären Proliferation maßgeblich von einer intakten KC-spezifischen NF-kB-Aktivität und nachfolgender Freisetzung pro-mitogener Stimuli, wie TNF-alpha und IL-6, abhängt. Darüber hinaus scheinen die KC durch die Modulation vasoaktiver Enzymsysteme an der Regulation des intrahepatischen Blutflusses und des intravaskulären Scherstresses als Triggermechanismus der Leberregeneration beteiligt zu sein.This study presents comprehensive data on hepatic architecture, microcirculation and cell integrity during liver regeneration after 70% resection. We showed that KC turn out to be essential for intact liver regeneration by stimulating cellular proliferation via NF-kB activation and effector downstream signals, such as TNF-alpha und IL-6 release. Additionally, with respect to their expression and modulation of vasoactive enzyme systems, KC are considered to be crucial for the local control of hepatic sinusoidal blood flow and intrahepatic shear stress as an initial trigger of hepatic proliferation

Multiple Doses of Erythropoietin Impair Liver Regeneration by Increasing TNF-α, the Bax to Bcl-xL Ratio and Apoptotic Cell Death

BACKGROUND: Liver resection and the use of small-for-size grafts are restricted by the necessity to provide a sufficient amount of functional liver mass. Only few promising strategies to maximize liver regeneration are available. Apart from its erythropoiesis-stimulating effect, erythropoietin (EPO) has meanwhile been recognized as mitogenic, tissue-protective, and anti-apoptotic pleiotropic cytokine. Thus, EPO may support regeneration of hepatic tissue. METHODOLOGY: Rats undergoing 68% hepatectomy received daily either high dose (5000 IU/kg bw i.v.) or low dose (500 IU/kg bw i.v.) recombinant human EPO or equal amounts of physiologic saline. Parameters of liver regeneration and hepatocellular apoptosis were assessed at 24 h, 48 h and 5 d after resection. In addition, red blood cell count, hematocrit and serum EPO levels as well as plasma concentrations of TNF-alpha and IL-6 were evaluated. Further, hepatic Bcl-x(L) and Bax protein expression were analyzed by Western blot. PRINCIPAL FINDINGS: Administration of EPO significantly reduced the expression of PCNA at 24 h followed by a significant decrease in restitution of liver mass at day 5 after partial hepatectomy. EPO increased TNF-alpha levels and shifted the Bcl-x(L) to Bax ratio towards the pro-apoptotic Bax resulting in significantly increased hepatocellular apoptosis. CONCLUSIONS: Multiple doses of EPO after partial hepatectomy increase hepatocellular apoptosis and impair liver regeneration in rats. Thus, careful consideration should be made in pre- and post-operative recombinant human EPO administration in the setting of liver resection and transplantation

TGF-β1 and TGF-β2 abundance in liver diseases of mice and men

TGF-β1 is a major player in chronic liver diseases promoting fibrogenesis and tumorigenesis through various mechanisms. The expression and function of TGF-β2 have not been investigated thoroughly in liver disease to date. In this paper, we provide evidence that TGF-β2 expression correlates with fibrogenesis and liver cancer development. Using quantitative realtime PCR and ELISA, we show that TGF-β2 mRNA expression and secretion increased in murine HSCs and hepatocytes over time in culture and were found in the human-derived HSC cell line LX-2. TGF-β2 stimulation of the LX-2 cells led to upregulation of the TGF-β receptors 1, 2, and 3, whereas TGF-β1 treatment did not alter or decrease their expression. In liver regeneration and fibrosis upon CCl4 challenge, the transient increase of TGF-β2 expression was accompanied by TGF-β1 and collagen expression. In bile duct ligation-induced fibrosis, TGF-β2 upregulation correlated with fibrotic markers and was more prominent than TGF-β1 expression. Accordingly, MDR2-KO mice showed significant TGF-β2 upregulation within 3 to 15 months but minor TGF-β1 expression changes. In 5 of 8 hepatocellular carcinoma (HCC)/hepatoblastoma cell lines, relatively high TGF-β2 expression and secretion were observed, with some cell lines even secreting more TGF-β2 than TGF-β1. TGF-β2 was also upregulated in tumors of TGFα/cMyc and DEN-treated mice. The analysis of publically available microarray data of 13 human HCC collectives revealed considerable upregulation of TGF-β2 as compared to normal liver. Our study demonstrates upregulation of TGF-β2 in liver disease and suggests TGF-β2 as a promising therapeutic target for tackling fibrosis and HCC

Regulation of hepatic blood flow: The hepatic arterial buffer response revisited

The interest in the liver dates back to ancient times when it was considered to be the seat of life processes. The liver is indeed essential to life, not only due to its complex functions in biosynthesis, metabolism and clearance, but also its dramatic role as the blood volume reservoir. Among parenchymal organs, blood flow to the liver is unique due to the dual supply from the portal vein and the hepatic artery. Knowledge of the mutual communication of both the hepatic artery and the portal vein is essential to understand hepatic physiology and pathophysiology. To distinguish the individual importance of each of these inflows in normal and abnormal states is still a challenging task and the subject of ongoing research. A central mechanism that controls and allows constancy of hepatic blood flow is the hepatic arterial buffer response. The current paper reviews the relevance of this intimate hepatic blood flow regulatory system in health and disease. We exclusively focus on the endogenous interrelationship between the hepatic arterial and portal venous inflow circuits in liver resection and transplantation, as well as inflammatory and chronic liver diseases. We do not consider the hepatic microvascular anatomy, as this has been the subject of another recent review

Repin1 deficiency in liver tissue alleviates NAFLD progression in mice

There is an increasing prevalence of obesity and metabolic syndrome, which promote the development of non–alcoholic fatty liver disease (NAFLD), a disease that can evolve into cirrhosis and hepatocellular carcinoma. Repin1 loss was previously shown to have beneficial effects on lipid and glucose metabolism and obesity regulation. Herein, we characterized NAFLD in mice with hepatic deletion of Repin1 (LRep1−/−). For this purpose, liver disease was analysed in male LRep1−/− and wild-type mice treated with streptozotocin/high fat diet or a control diet over a period of 20 wks. Streptozotocin/high fat diet treated LRep1−/− mice showed a significant decrease in systemic and hepatic lipid accumulation, accompanied by diminished chronic inflammation and a subsequent reduction in liver injury. Remarkably, Repin1-deficient mice exhibited a lower tumour prevalence and tumour frequency, as well as a reduced liver weight/body weight index. A therapeutic approach using Repin1 siRNA in the early phase of NAFLD verified the observed beneficial effects of Repin1 deficiency. This study provides evidence that loss of Repin1 in the liver attenuates NAFLD progression, most likely by reducing fat accumulation and alleviating chronic tissue inflammation. Thus, modulating Repin1 expression may become a novel strategy and potential tool to inhibit NAFLD progression. Keywords: Lipid accumulation, Metabolic disorder, siRNA, Non-alcoholic fatty liver disease, Fibrosis, Liver tumou

Anti-apoptotic Bcl-x_L and pro-apoptotic Bax as well as the Bcl-x_L/Bax ratio.

<p>Protein expression of anti-apoptotic Bcl-x_L (A) and pro-apoptotic Bax (B) as well as the Bcl-x_L/Bax ratio (C) in animals at 24 h, 48 h and 5 d after pHx and daily administration of high dose EPO (5000 IU/kg bw iv; closed bars) or physiologic saline solution (open bars). Data are normalized to ß-actin as loading control. Means±SEM; unpaired Student's t-test. * P<0.05 vs the saline-treated group at the respective time point.</p