that synchronize the regenerative response to liver injury Tumor necrosis factor a (TNF), initiates a cytokine and implies that hepatocytes and liver nonparenchymal cells cascade that promotes hepatocyte proliferation after are both the sources of, and the targets for, various growth-70% partial hepatectomy (PH) but the mechanisms reguregulatory cytokines. Thus, to understand how liver regenerlating TNF production after PH are unknown. We preation is regulated, it is critical to delineate the cytokine netviously reported that gadolinium chloride (GdCl), an works that modify the phenotypes of liver cells during this agent that depletes the liver of phagocytically active growth response. Kupffer cells, enhances hepatic expression of TNF mesSeveral lines of evidence suggest that tumor necrosis factor senger RNA (mRNA) and promotes liver regeneration (TNF) a, is likely to be a key component of the paracrine after subsequent PH. This suggests that GdCl interferes network that promotes hepatocyte proliferation during liver with Kupffer cell mechanisms that normally constrain TNF production after PH. To evaluate this, the pre-and regeneration. The possibility that TNF may play a hepatopost-PH expression of TNF, TNF-inducible cytokines (in-trophic role is somewhat counterintutitive, given its wellterleukin [IL]-1, IL-6) and cytokines (transforming documented cytotoxic effects in other settings.2 However, this growth factor [TGF] b 1 and IL-10) that down-regulate theory is supported by data which show that liver DNA syn-TNF were compared in controls and GdCl-treated rats. thesis and hepatocyte mitoses increase in healthy adult rats In controls, TNF, IL-1, IL-6, and IL-10 increase within 3 after intravenous administration of human recombinant hours after PH, whereas TGF-b 1 is induced much later TNF 3 and evidence that pretreatment of rats with neutraliz-(ú24 hours after PH). GdCl causes sustained overex-ing antibodies to TNF 4 or soluble TNF receptors (Rai RM, et pression of TNF mRNA and transient overexpression of al., Unpublished data, May 1996) inhibits hepatocyte DNA circulating TNF protein after PH; both TNF-inducible synthesis after PH. To date, the mechanisms which control cytokines are also relatively overexpressed. Cytokines TNF production during liver regeneration have not been that down-regulate TNF are effected differentially by characterized. GdCl. Regenerative induction of IL-10 is abolished butIsolated Kupffer cells are known to produce TNF when TGF-b 1 induction is unaltered. Because IL-10 is known to stimulated by lipopolysaccharide 5 and are generally preshorten the half-life of TNF mRNA, these results suggest sumed to be an important source of hepatic TNF during an that Kupffer cell production of IL-10 is an important inflammatory response.6 Thus, we were surprised to discover mechanism that down-regulates TNF production during that gadolinium chloride (GdCl), an agent that depletes the liver regeneration. (HEPATOLOGY 1997;25:889-895.) liver of phagocytically active Kupffer cells, 7 increases hepatic l...
Background & Aims: While altered host-microbe interactions are implicated in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), specific contributions of microbially derived metabolites remain obscure. We investigated the impact of altered bile acid (BA) populations on intestinal and hepatic phenotypes in a rodent model of NAFLD/NASH. Methods: Wistar rats fed a choline-deficient high-fat diet (CDAHFD) were assessed for altered intestinal permeability after dietary intervention. Cecal and portal venous BA composition were assessed via mass spectrometry. BA-mediated effects on epithelial permeability were assessed using Caco2 epithelial monolayers. Micelle formation was assessed using fluorescent probes and electron microscopy. Bile salt hydrolase (BSH) activity was inhibited with a gut-restricted small molecule in CDAHFD-fed rats and intestinal and hepatic phenotypes were assessed. Results: Increased intestinal permeability and reduced intestinal conjugated BAs were early phenotypes of CDAHFD-fed rats preceding hepatic disease development. Similar intestinal BA pool changes were observed in rats and human NAFLD/NASH patients with progressive disease. Conjugated BAs protected epithelial layers from unconjugated BA-induced damage via mixed micelle formation. The decrease in intestinal conjugated BAs was mediated by increased activity of bacterial BSHs and inhibition of BSH activity prevented the development of pathologic intestinal permeability and hepatic inflammation in the NAFLD/NASH model. Conclusions: Conjugated BAs are important for the maintenance of intestinal barrier function by sequestering unconjugated BAs in mixed micelles. Increased BSH activity reduces intestinal conjugated BA abundance, in turn increasing intestinal permeability and susceptibility to the development of NAFLD/NASH. These findings suggest that interventions that shift the intestinal bile acid pool toward conjugated BAs could be developed as therapies for NAFLD/NASH.
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