Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular Reaction

Richardson, Michelle M.; Jonsson, Julie R.; Powell, Elizabeth E.; Brunt, Elizabeth M.; Neuschwander‐Tetri, Brent A.; Bhathal, Prithi S.; Dixon, John; Weltman, Martin; Tilg, Herbert; Moschen, Alexander R.; Purdie, David M.; Demetris, Anthony J.; Clouston, Andrew D.

doi:10.1053/j.gastro.2007.05.012

Cited by 450 publications

(430 citation statements)

References 51 publications

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“…Previous studies have suggested that these responses go hand in hand, 4,22,35,36 and again in the present study, we have robustly demonstrated this correlation. We previously hypothesized that inflammatory infiltration precedes the progenitor cell response in CDE-fed mice, 32 and we more recently proposed that initiation of LPC proliferation stimulates activation of hepatic stellate cells and thus matrix remodeling.…”

Section: Discussionsupporting

confidence: 90%

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

Tirnitz–Parker¹,

Viebahn²,

Jakubowski³

et al. 2010

Hepatology

160

182

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Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte-mediated repair mechanisms are compromised. LPC proliferation is frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor–like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin–positive cells. Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation and dose-dependent proliferation, which was diminished after targeting of the p50 NFκB subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14-dependent and NFκB-dependent fashion, and signaling via this pathway mediates the LPC response to CDE-induced injury and regeneration. (Hepatology 2010)

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Section: Discussionsupporting

confidence: 90%

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

Tirnitz–Parker¹,

Viebahn²,

Jakubowski³

et al. 2010

Hepatology

160

182

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“…Improvement in hepatocellular ballooning is particularly important, as recent data support that ballooning, a feature of cell injury, is associated independently with fibrosis progression. 16 As illustrated in Figure 1, there seems to be a linear relationship with weight loss and improvement in the histologic index of activity, the NAS that continues with even greater amounts of weight loss. The mean NAS improved from 4.8 Ϯ 1.9 to 1.7 Ϯ 1.3 in those subjects who lost Ն9% of their body weight.…”

Section: Discussionmentioning

confidence: 89%

Orlistat for overweight subjects with nonalcoholic steatohepatitis

Fecht²,

et al. 2009

Self Cite

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The aim of this study was to determine if orlistat, an inhibitor of fat absorption, combined with caloric restriction in overweight subjects with nonalcoholic steatohepatitis results in weight loss and improved liver histology. Fifty overweight subjects (body mass index ‫؍‬ >27) with biopsy proven nonalcoholic steatohepatitis were randomized to receive a 1,400 Kcal/day diet plus vitamin E (800 IU) daily with or without orlistat (120 mg three times a day) for 36 weeks. Liver biopsies were repeated at week 36. Twenty-three subjects in the orlistat/diet/vitamin E group and 18 in the diet/vitamin E group completed the study. The mean age was 47 ؎ 9.0 (standard deviation) years and mean body mass index was 36.4 ؎ 6.3 kg/m 2 . Four subjects were diabetic. The orlistat group lost a mean of 8.3% body weight compared to 6.0% in the diet plus vitamin E group (not significant). Both groups also had similarly improved serum aminotransferases, hepatic steatosis, necroinflammation, ballooning, and nonalcoholic fatty liver disease activity scores. Stratified according to weight loss instead of treatment group, a loss of >5% body weight (n ‫؍‬ 24) compared to <5% body weight (n ‫؍‬ 17) correlated with improvement in insulin sensitivity (P ‫؍‬ 0.001) and steatosis (P ‫؍‬ 0.015). Comparing subjects who lost >9% of body weight (n ‫؍‬ 16), to those that did not (n ‫؍‬ 25), improved insulin sensitivity (P < 0.001), adiponectin (P ‫؍‬ 0.03), steatosis (P ‫؍‬ 0.005), ballooning (P ‫؍‬ 0.04), inflammation (P ‫؍‬ 0.045), and nonalcoholic fatty liver disease activity score (P ‫؍‬ 0.009) were seen. Increases in adiponectin strongly correlated with improved ballooning and nonalcoholic fatty liver disease activity score (P ‫؍‬ 0.03). Orlistat did not enhance weight loss or improve liver enzymes, measures of insulin resistance, and histopathology. However, subjects who lost >5% of body weight over 9 months improved insulin resistance and steatosis, and those subjects who lost >9% also achieved improved hepatic histologic changes. (HEPATOLOGY 2009;49:80-86.)

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“…4 Beside HSC, biliary cells represent an other potential target of EC during fibrogenesis. [20][21] In our non-cholestatic model, biliary cells proliferate along the fibrotic septa in cirrhotic livers as shown by the immunostaining for the specific CK-19 Figure 8 Immunostaining of hepatic cannabinoid type 1 (CB1) and CB2 receptors. Representative images of CB1 and CB2 receptor immunostained liver sections ( Â 20 outer and Â 40 inner) from healthy control rats (CT; a, c) and pre-ascitic cirrhotic rats (CH Basal ; b, d).…”

Section: Endocannabinoids and Liver Cirrhosismentioning

confidence: 86%

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

Giannone

Baldassarre

Domenicali

et al. 2012

Laboratory Investigation

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The endocannabinoid system is involved in the pathogenesis of liver fibrosis. Although many substances have been proved to reduce fibrosis in experimental models of chronic liver injury, most of them appear to be effective only if given as a prophylactic or early treatment. This study aimed to explore the effect of pharmacological antagonism of the endocannabinoid cannabinoid type 1 (CB1) receptor started after the stage of full-blown cirrhosis had been reached. Wistar-Han rats with carbon tetrachloride (CCl 4 )-induced cirrhosis were randomized to receive the CB1 receptor antagonist Rimonabant (10 mg/kg/day) or the vehicle for 2 weeks. Age-matched healthy rats served as controls. Liver fibrosis was assessed using Sirius red staining, hydroxyproline concentration and a-smooth muscle actin expression. Hepatic gene expression of mediators of fibrogenesis and inflammation were evaluated by real-time PCR. We also assessed the hepatic expression of CB1 and CB2 receptors and that of the enzymes implicated in the endocannabinoid metabolism. Fibrosis was significantly reduced in rats treated with Rimonabant compared with rats receiving the vehicle. CB1 receptor antagonism limited the gene upregulation of fibrogenic and inflammatory mediators occurring in untreated cirrhotic rats. CB1 and CB2 receptor expression was increased in cirrhotic animals. Interestingly, pharmacological CB1 receptor antagonism was associated with a further induction of the CB2 receptor expression. Regression of fibrosis can be achieved by pharmacological blockade of the CB1 receptor even when started in an advanced stage of the disease. This effect is associated with the suppression of pro-fibrogenic and inflammatory mediators and may have been indirectly favoured by the induction of CB2 receptor expression.

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Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular Reaction

Cited by 450 publications

References 51 publications

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

Tumor Necrosis Factor–Like Weak Inducer of Apoptosis Is a Mitogen for Liver Progenitor Cells

Orlistat for overweight subjects with nonalcoholic steatohepatitis

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

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