JunD is implicated in the regulation of hepatic stellate cell (HSC) activation and liver fibrosis via its transcriptional regulation of the tissue inhibitor of metalloproteinases-1 (TIMP-1) gene. In the present study we found in vivo evidence of a role for JunD in fibrogenesis. Expression of JunD was demonstrated in alpha-SMA-positive activated HSCs of fibrotic rodents and human livers. The junD −/− mice were protected from carbon tetrachloride–induced fibrosis. The livers of injured junD −/− mice displayed significantly reduced formation of fibrotic crosslinked collagen and a smaller number of alpha-SMA-positive HSCs compared with those of wild-type (wt) mice. Hepatic TIMP-1 mRNA expression in injured junD −/− mice was 78% lower and in culture activated junD −/− HSCs was 50%-80% lower than that in wt mice. In examining the signal transduction mechanisms that regulate JunD-dependent TIMP-1 expression, we found a role for phosphorylation of the Ser100 residue of JunD but ruled out JNK as a mediator of this event, suggesting ERK1/2 is utilized. In conclusion , a signaling pathway for the development of fibrosis involves the regulation of TIMP-1 expression by phosphorylated JunD. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
The failing Fontan circulation is associated with hepatic impairment. The nature of this liver injury is poorly defined.To establish the gross and histological liver changes of patients with Fontan circulation relative to clinical, biochemical and haemodynamic findings.Patients were retrospectively assessed for extracardiac Fontan conversion between September 2003 and June 2005, according to an established clinical protocol. Twelve patients, mean age 24.6 (range 15.8-43.4) years were identified. The mean duration since the initial Fontan procedure was 14.1 (range 6.9-26.4) years.Zonal enhancement of the liver (4/12) on CT was more common in patients with lower hepatic vein pressures (p = 0.007), and in those with absent cardiac cirrhosis on histological examination (p = 0.033). Gastro-oesophageal varices (4/12) were more common in patients with higher hepatic vein pressure (21 (6.3) vs 12.2 (2.2) mm Hg, p = 0.013) and associated with more advanced cirrhosis (p = 0.037). The extent of cirrhosis (7/12) was positively correlated with the hepatic vein pressure (r = 0.83, p = 0.003). A significant positive correlation was found between the Fontan duration and the degree of hepatic fibrosis (r = 0.75, p = 0.013), as well as presence of broad scars (r = 0.71, p = 0.021). Protein-losing enteropathy (5/12) occurred more frequently in patients with longer Fontan duration (11.7 (3.2) vs 17.9 (6.1) years, p = 0.038).Liver injury, which can be extensive in this patient group, is related to Fontan duration and hepatic vein pressures. CT scan assists non-invasive assessment. Cardiac cirrhosis with the risk of developing gastro-oesophageal varices and regenerative liver nodules, a precursor to hepatocellular carcinoma, is common in this patient group.
Collagen-I, which predominates in the neomatrix of fibrotic liver, regulates hepatocyte and hepatic stellate cell (HSC) phenotypes. Recovery from liver fibrosis is accompanied by hepatocyte regeneration, matrix degradation, and HSC apoptosis. Using mice bearing a mutated collagen-I gene (r/r mice), which confers resistance to collagenase degradation, we have investigated the hypothesis that collagen-I degradation is critical to HSC apoptosis and hepatocyte regeneration during recovery from liver fibrosis. During a 28-day recovery period after 8 wk of CCl4 treatment, wild-type (WT) livers had significantly (43%) decreased hydroxyproline (OHP) content. In r/r livers, however, OHP content remained elevated at peak fibrosis levels. Expressed markers of activated HSC (α-smooth muscle actin, collagen-I), elevated at peak fibrosis, dropped to control levels in WT livers after 28 days but remained raised in the r/r livers. Moreover, relative to WT livers, r/r livers had significantly reduced stellate cell apoptosis and hepatocyte regeneration during the recovery period. Using extracted collagen-I from each genotype as culture substrata, relative to r/r, we show that WT collagen-I promotes hepatocyte proliferation via stimulation of integrin αvβ3. Failure to degrade collagen-I critically impairs HSC apoptosis and may prevent the effective restoration of hepatocyte mass in liver fibrosis.
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