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The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65 years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3 years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P

Background Vitamin D deficiency is common in chronic liver disease particularly in those with severe liver fibrosis. Aims To determine the effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the human α1(I) collagen promoter and collagen formation by human stellate LX-2 cells and the mechanism of the effect of the vitamin D receptor ( VDR) on the promoter. Methods Type I collagen was assessed by measurements of collagen mRNA and collagen protein and by transfection experiments. Binding of VDR to the α1(I) collagen promoter was determined by EMSA and ChIP assays. Results 1,25-(OH)2D3 decreased human α1(I) collagen mRNA and protein and the secretion of type I collagen by stellate cells after exposure to TGFβ1. Furthermore, 1,25-(OH)2D3 inhibited TGFβ1-induced activation of the α1(I) collagen promoter in transfected LX-2 cells. The effect of 1,25-(OH)2D3 is mediated by the VDR, which binds at a proximal Sp1 site and also at a newly identified distal site on the collagen promoter. A VDR expression vector reduced the activities of the collagen promoter in transfected LX-2 cells. Conclusions 1,25-(OH)2D3 inhibits type I collagen formation in human stellate cells. The effect of 1,25-(OH)2D3 is mediated by its receptor which binds at a proximal Sp1.1 site and at a newly identified distal site on the collagen promoter. Correction of vitamin D deficiency in patients with chronic liver disease is a potential therapy to inhibit progression of fibrosis. [ABSTRACT FROM AUTHOR]

Background Doses of ethanol (EtOH) that are not overtly cytotoxic inhibit mitogen-induced hepatocyte proliferation and delay liver regeneration after 70% partial hepatectomy (PH). The mechanisms for this are poorly understood. This study evaluates the hypothesis that EtOH inhibits hepatocyte proliferation after PH by inducing redox-sensitive factors, such as p38 mitogen-activated protein kinase (MAPK) and p21 (WAF1/CIP1), that protect cells from oxidative stress but prevent cell-cycle progression by inhibiting cyclin D1. Methods Mechanisms that regulate the transition from the prereplicative G1 phase of the cell cycle into S phase were compared in EtOH-fed mice and normal pair-fed mice after PH. Results Prior EtOH exposure significantly increases p38 MAPK and p21 after PH. This is accompanied by reduced expression of cyclin D1 messenger RNA and protein, increases in other cell-cycle regulators (such as signal transducer and activator of transcription-3 and p27) that are normally inhibited by cyclin D1, and hepatocyte G1 arrest. Conclusions EtOH amplifies G1 checkpoint mechanisms that are induced by oxidative stress and promotes hepatic accumulation of factors, including p38 MAPK, p21, and signal transducer and activator of transcription-3, that enhance cellular survival after oxidant exposure. Therefore, cell-cycle inhibition may be an adaptive response that helps EtOH-exposed livers survive situations, such as PH, that acutely increase reactive oxygen species in hepatocytes. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a progressive pathologic process that involves deposition of excess extracellular matrix leading to distorted architecture and culminating in cirrhosis. The role of transforming growth factor-β (TGF-β) as a key molecule in the development and progression of hepatic fibrosis via the activation of hepatic stellate cells, among other fibroblast populations, is without controversy. We hereby show that TGF-β1 induces an epithelial-to-mesenchymal transition (EMT) state in mature hepatocytes in vitro. EMT state was marked by significant up-regulation of α1(I) collagen mRNA expression and type I collagen deposition. Similar changes were found in a "normal" mouse hepatocyte cell line (AML12), thus confirming that hepatocytes are capable of EMT changes and type I collagen synthesis. We also show that in hepatocytes in the EMT state, TGF-β1 induces the snail-1 transcription factor and activates the Smad2/3 pathway. Evidence for a central role of the TGF-β1/Smad pathway is further supported by the inhibition of EMT by Smad4 silencing using small interference RNA technology. In conclusion, TGF-β1, a known pro-apoptotic cytokine in mature hepatocytes, is capable of mediating phenotypic changes and plasticity in the form of EMT, resulting in collagen deposition. Our findings support a potentially crucial role for EMT in the development and progression of hepatic fibrogenesis. [ABSTRACT FROM AUTHOR]

Background: Vitamin D deficiency is common in chronic liver disease particularly in those with severe liver fibrosis., Aims: To determine the effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ) on the human α(1) (I) collagen promoter and collagen formation by human stellate LX-2 cells and the mechanism of the effect of the vitamin D receptor (VDR) on the promoter., Methods: Type I collagen was assessed by measurements of collagen mRNA and collagen protein and by transfection experiments. Binding of VDR to the α(1) (I) collagen promoter was determined by EMSA and ChIP assays., Results: 1,25-(OH)2 D3 decreased human α(1) (I) collagen mRNA and protein and the secretion of type I collagen by stellate cells after exposure to TGFβ1. Furthermore, 1,25-(OH)2 D3 inhibited TGFβ1-induced activation of the α(1) (I) collagen promoter in transfected LX-2 cells. The effect of 1,25-(OH)2 D3 is mediated by the VDR, which binds at a proximal Sp1 site and also at a newly identified distal site on the collagen promoter. A VDR expression vector reduced the activities of the collagen promoter in transfected LX-2 cells., Conclusions: 1,25-(OH)2 D3 inhibits type I collagen formation in human stellate cells. The effect of 1,25-(OH)2 D3 is mediated by its receptor which binds at a proximal Sp1.1 site and at a newly identified distal site on the collagen promoter. Correction of vitamin D deficiency in patients with chronic liver disease is a potential therapy to inhibit progression of fibrosis., (© 2013 John Wiley & Sons A/S.)

Unlabelled: Transforming growth factor beta1 (TGFbeta1) plays a crucial role in the induction of the epithelial-to-mesenchymal transition (EMT) in hepatocytes, which contributes to the pathogenesis of liver fibrosis. The inhibition of the TGFbeta1 cascade suppresses EMT and the resultant fibrosis. In this study, we focus on EMT-induced fibrosis in hepatocytes and the epigenetic regulation of the type I collagen gene. Histone acetylation is an important, major epigenetic mechanism that modulates gene transcription. We evaluated the epigenetic regulation of type I collagen in alpha mouse liver 12 hepatocytes (an untransformed mouse cell line) that had undergone EMT after treatment with TGFbeta1. The histone deacetylase inhibitor trichostatin A (TSA) inhibited EMT; this was reflected by the preservation of epithelial markers and function (E-cadherin and albumin). Fibrosis, the ultimate outcome of EMT, was abolished by TSA; this was indicated by the inhibition of type I collagen deposition. TSA exerted its anti-EMT effects by deactivating the mothers against decapentaplegic homolog 3 (Smad3)/Smad4 transcription complex and by interfering with p300, a coactivator of the type I collagen promoter, and preventing its binding to Smad3. TSA also restored Friend leukemia virus integration 1, an inhibitor of the type I collagen gene. TGFbeta1-induced EMT and its inhibition by TSA were replicated in human primary hepatocytes., Conclusion: Histone deacetylase inhibition abrogates TGFbeta1-induced EMT in hepatocytes and reverses EMT-induced fibrosis by epigenetic modulation of type I collagen.

We undertook a retrospective analysis of colonic spirochetosis in 14 cases: females, 3; males, 11; children, 4; adults, 10. Two men had HIV infections. All children and both HIV-infected men had abdominal complaints, diarrhea, or both. Most other adults underwent colonoscopy for polyp screening (n = 4) or follow-up of Crohn disease (n = 1) or had other indications (n = 2) or diarrhea (n = 1). Histologically, spirochetosis was identified in all parts of the colon and was not strongly associated with active inflammation, mucosal injury, or changes of chronicity. Genotype analysis of 13 cases showed that 11 resulted from Brachyspira aalborgi and 2 from Brachyspira pilosicoli infections. Only 2 patients were treated specifically with antibiotics, with complete resolution of abdominal symptoms in 1 patient with follow-up. Follow-up biopsy result were available for 2 patients who did not receive treatment; one showed persistent spirochetosis, and the other was negative. Spirochetosis in this series had a male predominance, was generally caused by B aalborgi, and occurred in 2 distinct clinical settings: children who often have abdominal symptoms and adults who typically are asymptomatic. While treatment information remains limited, treatment can lead to resolution of symptoms in some cases.

Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNFalpha to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNFalpha, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4-5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-kappaB and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.