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Lipid Accumulation in Hepatocytes Induces Fibrogenic Activation of Hepatic Stellate Cells

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Lipid Accumulation in Hepatocytes Induces Fibrogenic Activation of Hepatic Stellate Cells npg In vitro model for steatosis induced fibrogenesis Cell Research (2009) 19:996-1005. 996 npg © 2009 IBCB, SIBS, CAS All rights reserved 1001-0602/09 $ 32.00 ORIGINAL ARTICLE www.nature.com/cr Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells Hella Wobser1, *, Christoph Dorn1, *, Thomas S Weiss2, Thomas Amann1, Cornelius Bollheimer1, Roland Büttner1, Jürgen Schölmerich1, Claus Hellerbrand1 1Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany; 2Center for Liver Cell Research, Department of Surgery, University of Regensburg, D-93042 Regensburg, Germany Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of other liver diseases. Here, we established an in vitro model to study the effect of hepatic lipid accumulation on hepatic stellate cells (HSCs), the central mediators of liver fibrogenesis. Primary human hepatocytes were incubated with the saturated fatty acid palmitate to induce intracellular lipid accumulation. Subsequently, human HSCs were incubated with conditioned media (CM) from steatotic or control hepatocytes. Lipid accumulation in hepatocytes induced the release of factors that accelerated the activation and proliferation of HSC, and enhanced their resistance to apoptosis, largely mediated via activation of the PI-3-kinase pathway. Furthermore, CM from steatotic hepatocytes induced the expression of the profibrogenic genes TGF-β, tissue inhibitor of metallo-proteinase-1 (TIMP-1), TIMP-2 and matrix-metallo-proteinase-2, as well as nuclear-factor κB-dependent MCP-1 expression in HSC. In summary, our in vitro data indicate a potential mechanism for the pathophysiological link between hepatic steatosis and fibrogenesis in vivo. Herewith, this study provides an attractive in vitro model to study the molecular mechanisms of steatosis-induced fibrogenesis, and to identify and test novel targets for antifibrotic therapies in fatty liver disease. Keywords: fibrosis, hepatic stellate cells, non-alcoholic fatty liver disease, steatosis,in vitro model Cell Research (2009) 19:996-1005. doi: 10.1038/cr.2009.73; published online 23 June 2009 Introduction non-alcoholic steatohepatitis (NASH) that leads to liver fibrosis and finally cirrhosis [1]. Recent reports about Non-alcoholic fatty liver disease (NAFLD) has cryptogenic cirrhosis most likely representing “burned- emerged as a considerable public health concern as its out NASH” further support its potentially progressive major risk factors, that is, obesity and insulin resistance, nature [2]. Once cirrhosis has developed, the mortality seem to reach epidemic proportions worldwide. Histolog- rate increases significantly due to a high risk of hepatic ical studies of biopsies taken from patients with NAFLD decompensation and hepatocellular carcinoma [3]. indicate that a significant number of patients progress to According to the two-hit-hypothesis of NASH, he- patic steatosis (“first hit”) is a prerequisite for subsequent events (“second hits”), involving environmental and genetic factors that lead to liver injury [4]. Free fatty *These authors contributed equally to this work. Correspondence: Claus Hellerbrand acids (FFAs) appear to be the major mediators of exces- Tel: +49-941-944-7155; Fax:+49-941-944-7154 sive hepatic lipid accumulation. The rate of hepatic FFA E-mail: [email protected] uptake is not regulated, and therefore, is proportional Abbreviations: CM (conditioned medium); FFAs (free fatty acids); HSC to plasma FFA concentrations [5]. In humans with NA- (hepatic stellate cells); NAFLD (non-alcoholic fatty liver disease); NASH (non-alcoholic steatohepatitis); MMP (matrix-metallo-proteinase); NFκB FLD, circulating FFAs are commonly elevated, and their (nuclear-factor κB); PHH (primary human hepatocytes); TIMP-1/-2 (tissue plasma levels correlate with disease severity [6]. Hepatic inhibitor of metallo-proteinase-1/-2) injury may occur when the capacity of hepatocytes to Received 4 September 2008; revised 2 January 2009; accepted 15 February safely store excess FFA in form of TGs in lipid droplets 2009; published online 23 June 2009 Cell Research | Vol 19 No 8 | August 2009 Hella Wobser et al. npg 997 is exceeded. Oxidative stress, mitochondrial dysfunction accumulation of cytosolic lipid droplets in primary and upregulation of pro-inflammatory cytokines (“second human hepatocytes (PHHs), as detected by confocal hits”) have been suggested to be major consequences of microscopy after staining with Oil Red O (Figure 1A). cellular lipid overload [7-9], potentially contributing to These findings were confirmed by colorimetric quanti- inflammatory liver damage and fibrogenesis in NASH. fication of the intracellular TG concentration in hepato- Of note, hepatic steatosis has been identified as a risk cytes exposed to 0.1-0.4 mM palmitate (Figure 1B). We factor for the progression of hepatic fibrosis in a wide found a 2.1-fold increase (± 0.13; P = 0.0023) in neutral range of liver diseases including alcoholic liver disease, lipid content after incubation with 0.1 mM palmitate chronic hepatitis C and hemochromatosis [10, 11]. compared to BSA-treated control cells. Lipid accumula- Current evidence indicates that hepatic stellate cells tion was even more pronounced after exposure to 0.2 or (HSCs) are central mediators of hepatic fibrosis. During 0.4 mM palmitate for 24 h (7.3 ± 0.41-fold and 11.6 ± hepatic injury, HSCs undergo a phenotypic transforma- 0.6-fold increase over control). tion from a quiescent retinoid-storing cell to a highly Measurement of the (residual) palmitate concentration proliferative myofibroblast-like celltype, a process in the supernatant revealed a complete uptake of palmi- termed activation. Activated HSCs express large amounts tate by hepatocytes incubated for 24 h with palmitate at of extracellular matrix (ECM), including collagen type I, a concentration of 0.1 or 0.2 mM. After 24-h incubation fibronectins and proteoglycans. Deposition of ECM is further enhanced by the production of tissue inhibitors of metalloproteinases (TIMP), which prevent the degra- A dation of ECM, leading to a net accumulation of ECM I II III IV with a gradual disruption of normal liver architecture. During liver injury, activated HSCs also release a large number of cytokines among which TGF-β is considered as the main fibrogenic cytokine. De novo expression of 10 mM pro-inflammatory cytokines and chemokines further en- hances hepatic fibrogenesis by recruiting leukocytes and perpetuating the inflammatory response [12, 13]. Finally, B 12.5 * it is also generally assumed that soluble mediators, se- 10.0 * creted by hepatocytes, contribute to the stimulation and 7.5 activation of HSC in chronic liver diseases [10, 14]. 5.0 (control set 1) In order to better understand the pathogenesis of Intracellular 2.5 * NAFLD/NASH and to identify factors involved in its triglyzeride content 0.0 progression to fibrosis, we aimed to establish an in vitro 0 0.1 0.2 0.4 Palmitate (mM) model to study the molecular mechanisms linking he- C patic steatosis to fibrogenesis. I II III IV Results 200 mM Palmitate treatment induces cellular lipid accumulation D in hepatocytes I Palmitate (C16:0) is the most prevalent long-chain saturated FFA found in circulation. It is bound to albu- min, with a physiological ratio of fatty acid to albumin 50 mM of approximately 2:1. In states of insulin resistance and obesity (as major risk factors for NAFLD/NASH), serum Figure 1 Intracellular lipid accumulation and lack of cytotoxic ef- fatty acid levels are commonly elevated, yielding ratios fects in hepatocytes after stimulation with palmitate. Primary hu- as high as 7.5:1 [15]. man hepatocytes (PHHs) were incubated with increasing palmi- In order to investigate the effect of hepatic steatosis tate concentrations (II: 0.1 mM, III: 0.2 mM, and IV: 0.4 mM) for on HSC, we established a palmitate-induced in vitro fatty 24 h. I: Cells treated with 0.4% (w/v) FFA-free BSA served as controls. (A) Oil red O staining. (B) Colorimetric assessment of liver model. Palmitate was complexed to BSA in a molar intracellular lipid content. (*P < 0.05 compared to control). (C) ratio of 6.7:1, thereby mimicking hyperlipidemic condi- Phase-contrast images of PHH cultures. (D) Chromatin staining tions. Exposure to palmitate induced a dose-dependent (Hoechst) www.cell-research.com | Cell Research npg In vitro model for steatosis induced fibrogenesis 998 with 0.4 mM palmitate, approximately 85% of the FFA in the supernatant of steatotic hepatocytes and to allow was taken up by the hepatocytes (data not shown). the potential substitution of PHH by hepatoma cells Viability of PHHs was not affected by the stimula- for the planned in vitro model (see below), we selected tion with increasing doses of palmitate (0.1-0.4 mM) as palmitate at a concentration of 0.2 mM for the subse- judged by microscopical analysis (Figure 1C), and the quent studies. assessment of the release of LDH and transaminases into Here, we generated conditioned media (CM) from the culture medium (data not shown). Furthermore, nu- PHH from the same donor stimulated with either 0.2 mM clear staining revealed no significant signs of apoptosis palmitate or BSA as control. Subsequently, the effects of (i.e. chromatin condensation and fragmentation) even at both CM on HSCs were compared. the highest palmitate concentration (0.4 mM; Figure 1D). In contrast to PHH and similarly as reported by Malhi Conditioned medium of steatotic hepatocytes accelerates et al. [16], HepG2 and Huh7 hepatoma cell lines showed HSC activation and profibrogenic gene expression of signs of lipotoxicity after stimulation with palmitate at HSC concentrations higher than 0.2 mM (data not shown). Initially, we aimed to analyze the effect of steatotic Hence, to exclude a direct effect of residual palmitate hepatocytes on the in vitro activation process of HSC.
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