27 Internalization was measured by the loss of surface expression of the receptor (as see more in our study) and has also been seen in response to partial GLP-1R agonists.28 Although the confocal data are convincing and corroborate with our blots from the membrane and nuclear fractions, the immunoblot data regarding transfer of GLP-1R to the cytoplasmic fraction is not as robust as visualized in the confocal data. Future work to clarify the internalization results will need to be performed but are beyond the scope of the present study. New techniques may be feasible; for example, self-labeling protein

tags that are covalently linked with fluorophores and selectively label the specific pool of GPCRs present at the plasma membrane without labeling any of the internal pools. Thus, a nonpermeable labeled substrate will label only the plasma membrane–bound GPCR proteins. This selective labeling approach may significantly reduce the signal intensity obtained by the confocal microscopic examination of cells performed with exendin-4, as we have demonstrated

here. Although we have demonstrated the hepatic GLP-1 receptor can be internalized, the data cannot quantify the degree to which exendin-4 induces this process. Although we recognize that much of the work performed in this study was in transformed malignant hepatocyte Selleckchem BTK inhibitor cell lines (primarily Huh7 cells), the identification of GLP-1R was also performed in primary human hepatocytes. We suspect that one of the reasons that some (but not all) previous studies have not identified GLP-1R is the availability of better quality antibodies against 上海皓元医药股份有限公司 the receptor and both the purity and availability of viable human hepatocytes for in vitro experimentation. These data are exciting

from a clinical and translational perspective, because they offer a plausible explanation as to why GLP-1 or GLP-like proteins may be beneficial in the treatment of the metabolic syndrome and NAFLD in particular. Importantly, these data indicate a direct effect of GLP-1 protein, as opposed to an indirect or pleotropic effect. As has been recently reported, patients undergoing bariatric surgery are found to have higher circulating levels of GLP-1 with significant histological improvement in their livers,29-32 especially those who undergo ileal transposition.31 In the present study, we provide evidence for direct cellular effects of GLP-1 proteins by potentiating hepatocyte steatosis in vitro by supplementing Huh7 cells with palmitic and oleic acids and gauging the reduction of steatosis by Oil Red O staining and supportive TG quantification. Flow cytometric analysis demonstrated that methionine-choline–deficiency increased cellular neutral lipid content, which was significantly decreased by exendin-4 treatment.

This study in 102 patients with acute PVT prospectively enrolled over a period of 2 years clarifies manifestations, etiology, and outcome of anticoagulation therapy in this disease. Previously reported studies on acute PVT (most of them coming from centers participating to this consortium)8, 10, 11 yielded relatively consistent results which have based the current recommendation for management.2 However, these and subsequent studies7, 9, 16 all suffered from limitations that questioned the validity

of their interpretation, and inspired the design of the present collaborative study. First, the number of patients BGB324 mw given anticoagulation therapy was low (27 in the largest of these former studies).11 Second, the time period for patients’ accrual spanned 7 to 17 years. Third, a formal evaluation of the initial aspect of acute thrombosis and of the extent of the obstructed segments was not LY2606368 concentration based on predefined standardized criteria and expert review. Fourth, investigations for causes were neither comprehensive, nor did they always use the most accurate tests (such as the assessment of V617F JAK2 mutation). Finally, a referral bias in tertiary

centers could not be ruled out, whereas the present study was based on patients’ identification through nationwide networks. Our study is a prospective, multicenter European study including 4 times as many patients as any of the previous studies, in a defined period of 2 years. All patients had a clearly visible thrombus in the absence of cavernoma (which usually develops in a few weeks in the absence of recanalization) and most had symptoms of an acute illness. Although extension of the thrombus was not a criterion

for inclusion, enrolled patients suffered from a severe form of the disease. Indeed, the extrahepatic portal vein was completely blocked in approximately 90% of patients who were thus at risk of permanent portal hypertension. Furthermore, two-thirds of the patients had superior mesenteric vein involvement and were thus at of risk intestinal infarction. The present cohort differs from previous reports by a yet unnoticed, high prevalence of ascites and spleen enlargement. This finding is probably related in a large part to a systematic central review of images. Ascitic fluid was frequently detected at early imaging, although clinically detectable ascites was rare. Ascites has been reported MCE to herald intestinal infarction in patients with mesenteric vein thrombosis,17 which was confirmed in the present study with respect to clinically detectable ascites, although not with ascites that could be detected only at imaging. Spleen enlargement was shown here to be related in part to an underlying MPD, and possibly to acute congestion. Liver biopsy was not routinely performed for obvious ethical reasons in candidates for early anticoagulation. However, underlying cirrhosis was ruled out as an explanation for ascites and spleen enlargement.

Over an average of 7.7 years, 296 participants developed HCC (n = 125), GBTC (n = 137), or IBD (n = 34). Using risk-set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, and time of

blood collection. Baseline XL765 serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured, and incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection, and adiposity measures, higher concentrations of CRP, IL-6, C-peptide, and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations = 1.22; 95% CI = 1.02-1.46; P = 0.03; 1.90; 95% CI = 1.30-2.77; P = 0.001; 2.25; 95% CI = 1.43-3.54; P = 0.0005; and 2.09; 95% CI = 1.19-3.67; P = 0.01, respectively). CRP was associated also with risk of GBTC (IRR = 1.22; Roxadustat concentration 95% CI = 1.05-1.42;

P = 0.01). GLDH was associated with risks of HCC (IRR = 1.62; 95% CI = 1.25-2.11; P = 0.0003) and IBD (IRR = 10.5; 95% CI = 2.20-50.90; P = 0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide, and non-HMW adiponectin and 0.46 for GLDH, indicating good predictive ability of these biomarkers. Conclusion: Elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a MCE公司 higher risk of HCC, independent of obesity and established liver cancer risk factors. (Hepatology 2014;60:858–871) “
“Background and Aim:  Hepatitis C virus (HCV) is a common chronic infection that is widely associated with symptoms

of fatigue and abdominal pain. The aim of the present study was to determine the prevalence of irritable bowel syndrome (IBS) among patients with hepatitis C compared to controls. Methods:  This study included 258 patients with chronic hepatitis C, 36 patients with chronic hepatitis B, and 160 healthy volunteers. Clinical and laboratory data were recorded for every patient. All patients and controls were administered a questionnaire of IBS according to Rome III criteria. Results:  The percentage of patients with IBS was significantly higher in patients with chronic HCV (66%, 170/258) than chronic hepatitis B virus (HBV; 22%, 8/36) and normal controls (18%, 28/160 patients; P < 0.001 and P < 0.001, respectively). There was no significant difference between chronic HBV and normal controls. In chronic HCV patients, IBS with constipation was the predominant type (51%, 86/170) followed by mixed IBS (73/170, 43%).

It should be noted that our study, using Cyp7a1-tg mice as a model, does not necessarily contradict results from other bile-acid–treated experimental models because we have shown that increasing de novo bile acid synthesis did not result in bile acid accumulation in the liver, likely as a result of efficient bile acid secretion. Finally, this study identified that a novel miR-33a-mediated repression of CYP7A1, as a result of SREBP2 induction, could be part of the feedback loop to reduce bile acid synthesis. Alectinib The recent discovery of coexpression of SREBP2 and miR-33a, as well as down-regulation of ABCA1 by miR-33a, provided the first evidence that miR-33a down-regulates

cellular cholesterol efflux to HDL in response to decreased cellular cholesterol levels to maintain hepatic lipid homeostasis.[9] Our study provides further evidence that miR-33a inhibition of CYP7A1 and bile acid synthesis may also contribute to maintaining cholesterol homeostasis. Cholesterol/oxysterols might also repress miR-33a levels to increase CYP7A1 expression as well as cholesterol efflux transporters.[9] Figure 6 shows a proposed mechanism for the regulation of cholesterol homeostasis by a CYP7A1/SREBP2/miR-33a axis, based on this study, and the selleck inhibitor well-recognized mechanism for maintaining cholesterol homeostasis and pool by intracellular cholesterol or oxysterol levels.[8]

Increased CYP7A1 enzyme activity results in increased cholesterol catabolism and decreased intracellular cholesterol, which leads to proteolytic

activation of SREBP2 and subsequent stimulation of de novo cholesterol synthesis and LDLR-mediated cholesterol uptake to reduce serum cholesterol. Simultaneously, SREBP2 activation of its own gene transcription coinduces miR-33a, which down-regulates cholesterol efflux transporters and bile acid synthesis. These changes result in increased intrahepatic cholesterol, which subsequently represses SREBP2 and miR-33a expression. This mechanism integrates bile acids and cholesterol metabolism to control lipid homeostasis at both transcriptional and posttranscriptional levels. Thus, CYP7A1 may play a central role in sensing intracellular cholesterol 上海皓元 levels by converting excess hepatic cholesterol to bile acids, thus activating SREBP2 and miR-33a, which inhibits CYP7A1 translation as a rapid feedback mechanism. Inducing CYP7A1 activity by targeting miR-33a may be a potential therapeutic approach to improve metabolic homeostasis. This study suggests that the cardioprotective effects of miR-33a antagonism can be attributed not only to stimulating HDL biogenesis, but also bile acid synthesis, the final step in macrophage-to-feces reverse cholesterol transport. In this study, we also showed that mRNA of CYP8B1, NTCP, and BSEP were repressed upon miR-33a overexpression in mice, indicating that miR-33a antagonism also stimulates enterohepatic bile acid circulation.

It should be noted that our study, using Cyp7a1-tg mice as a model, does not necessarily contradict results from other bile-acid–treated experimental models because we have shown that increasing de novo bile acid synthesis did not result in bile acid accumulation in the liver, likely as a result of efficient bile acid secretion. Finally, this study identified that a novel miR-33a-mediated repression of CYP7A1, as a result of SREBP2 induction, could be part of the feedback loop to reduce bile acid synthesis. MK-1775 nmr The recent discovery of coexpression of SREBP2 and miR-33a, as well as down-regulation of ABCA1 by miR-33a, provided the first evidence that miR-33a down-regulates

cellular cholesterol efflux to HDL in response to decreased cellular cholesterol levels to maintain hepatic lipid homeostasis.[9] Our study provides further evidence that miR-33a inhibition of CYP7A1 and bile acid synthesis may also contribute to maintaining cholesterol homeostasis. Cholesterol/oxysterols might also repress miR-33a levels to increase CYP7A1 expression as well as cholesterol efflux transporters.[9] Figure 6 shows a proposed mechanism for the regulation of cholesterol homeostasis by a CYP7A1/SREBP2/miR-33a axis, based on this study, and the Selleckchem BAY 57-1293 well-recognized mechanism for maintaining cholesterol homeostasis and pool by intracellular cholesterol or oxysterol levels.[8]

Increased CYP7A1 enzyme activity results in increased cholesterol catabolism and decreased intracellular cholesterol, which leads to proteolytic

activation of SREBP2 and subsequent stimulation of de novo cholesterol synthesis and LDLR-mediated cholesterol uptake to reduce serum cholesterol. Simultaneously, SREBP2 activation of its own gene transcription coinduces miR-33a, which down-regulates cholesterol efflux transporters and bile acid synthesis. These changes result in increased intrahepatic cholesterol, which subsequently represses SREBP2 and miR-33a expression. This mechanism integrates bile acids and cholesterol metabolism to control lipid homeostasis at both transcriptional and posttranscriptional levels. Thus, CYP7A1 may play a central role in sensing intracellular cholesterol medchemexpress levels by converting excess hepatic cholesterol to bile acids, thus activating SREBP2 and miR-33a, which inhibits CYP7A1 translation as a rapid feedback mechanism. Inducing CYP7A1 activity by targeting miR-33a may be a potential therapeutic approach to improve metabolic homeostasis. This study suggests that the cardioprotective effects of miR-33a antagonism can be attributed not only to stimulating HDL biogenesis, but also bile acid synthesis, the final step in macrophage-to-feces reverse cholesterol transport. In this study, we also showed that mRNA of CYP8B1, NTCP, and BSEP were repressed upon miR-33a overexpression in mice, indicating that miR-33a antagonism also stimulates enterohepatic bile acid circulation.

The basis for these differences in the response to fatty liver injury are not known, although it has been noted

that young boys with NAFLD are particularly likely to demonstrated zone 1-based pathology.7 Our results identify a role for maturation-related differences in the Hh pathway in this variability. Hh pathway activity is generally low in healthy adult livers, but robust during embryogenesis. Here we demonstrate that over the course of mouse liver development, Hh Protein Tyrosine Kinase inhibitor signaling is gradually down-regulated as organogenesis is completed. Hence, cells that produce and/or respond to Hh are largely restricted to tissue progenitor compartments in adulthood. The main hepatic progenitor compartment in adults is based periportally within the vestiges of the fetal liver ductal plate (dubbed GSK126 in vivo the canals of Hering).20–22 Human liver progenitors are Hh-responsive, and rare Gli2-positive cells have been demonstrated in the livers of healthy adults.10 The livers of healthy children harbor greater numbers of Hh-responsive cells than the livers of healthy adults.14 Our new findings support the concept that the transition from a childhood complement

of Hh-responsive liver progenitors to an adult complement of Hh-responsive progenitors occurs during puberty. This interpretation is supported by our new evidence that in healthy, prepubescent male mice, Hh-responsive progenitors decline to adult levels during postweaning sexual maturation. It is also consistent with the fact that human liver development is completed during adolescence.15, 16 An important, disease-pertinent implication of our discovery is that Hh-mediated, progenitor-based repair responses to liver injury are much more robust in prepubertal children than in adults. Hh pathway activation has been shown to stimulate outgrowth of immature ductular-type progenitors and myofibroblasts (the

fibroductular reaction) and consequent liver fibrosis. In adults, the intensity of these Hh-mediated repair responses generally parallels the severity of liver injury because wounded hepatocytes produce Hh ligands, and release them as they die. Thus, hepatocyte ballooning, Hh pathway activity, portal inflammation, and liver fibrosis are all tightly correlated in adults with NAFLD.13 In young children with NAFLD, however, we demonstrated that cells in the from progenitor compartment (ductular cells and periportal hepatocytes) produce Hh ligands and showed that large numbers of Hh-responsive (Gli2-positive) cells accumulate there even when parenchymal liver injury is relatively minor (as evidenced by relatively rare ballooned hepatocytes). These findings suggest that the relatively primitive, childhood progenitor compartment is readily mobilized in response to fatty liver injury. As in adults, Hh pathway activation in children provoked portal-based inflammation, and a fibroductular reaction that resulted in local accumulation of fibrous scar.

2A). The numbers of detectable liver nodules ranged from PKC412 in vivo 21-47 per 50 mm2 section in treated mice and were never detected in controls. Nodules represent the clonal expansion of a single corrected hepatocyte, thus nodule frequency must be corrected for nodule size. For this experiment, the correction factor was estimated to be fourteen. After correction, the initial gene repair frequency ranged from 1/6,300 to 1/11,600 hepatocytes and was within the expected range from previous experiments15 where selection with NTBC did not apply. To demonstrate that FAH staining was not artifactual and that proper Fah gene expression had indeed been restored, Fah RT-PCR

was performed on RNA from treated livers. The presence of correctly spliced mRNA was demonstrated in all treated mice (Fig. 2B). To further demonstrate the stability of correction, 3 × 105 random hepatocytes from a corrected mouse were serially transplanted into four secondary adult Fah5981SB recipients. Serial transplantation is another means to induce hepatocyte turnover and eliminate episomal AAV genomes.35 Serial transplant recipients had successful engraftment and displayed clinical improvement, whereas untransplanted controls showed continuous weight loss and died. FAH immunohistochemistry

from livers of serial transplant recipients had extensive hepatocellular FAH staining, further demonstrating stability of the gene repair (Fig. MLN0128 supplier 2A). AAV8 is the preferred serotype for liver transduction because of its strong hepatic tropism, rapid capsid disassembly and genome release.36 In contrast, although AAV2 has been shown to transduce liver, it is characterized by slow capsid disassembly and genome release. To address the question whether to AAV serotypes 8 and 2 have different gene repair dynamics in vivo, d3 Fah5981SB neonates were treated

with 2 × 1011 vg of AAV8-Fah or 1 × 1011 vg of AAV2-Fah and analyzed after 1, 2, or 4 weeks post-treatment for the presence of FAH+ hepatocytes (Fig. 3). In AAV8-Fah treated mice, the highest number of FAH+ hepatocytes seen (up to 1/180 hepatocytes) were detected within the first week post-treatment. Correction frequencies declined with time and stabilized after 4 weeks. In contrast, AAV2-treated mice had little detectable Fah expression within the first seven days, supporting the fact that AAV2 uncoats more slowly than AAV8. Week two showed an increase in Fah expression that remained stable until week four. No FAH+ hepatocytes were detected at any time point in control mice injected with serotype-matched irrelevant control vectors AAV8-GFP or AAV2-hAAT at equivalent doses. These results conclusively demonstrate that emergence of FAH+ hepatocytes were neither due to spontaneous reversion, nor gene repair stimulated non-specifically by mere AAV transduction.

2A). The numbers of detectable liver nodules ranged from check details 21-47 per 50 mm2 section in treated mice and were never detected in controls. Nodules represent the clonal expansion of a single corrected hepatocyte, thus nodule frequency must be corrected for nodule size. For this experiment, the correction factor was estimated to be fourteen. After correction, the initial gene repair frequency ranged from 1/6,300 to 1/11,600 hepatocytes and was within the expected range from previous experiments15 where selection with NTBC did not apply. To demonstrate that FAH staining was not artifactual and that proper Fah gene expression had indeed been restored, Fah RT-PCR

was performed on RNA from treated livers. The presence of correctly spliced mRNA was demonstrated in all treated mice (Fig. 2B). To further demonstrate the stability of correction, 3 × 105 random hepatocytes from a corrected mouse were serially transplanted into four secondary adult Fah5981SB recipients. Serial transplantation is another means to induce hepatocyte turnover and eliminate episomal AAV genomes.35 Serial transplant recipients had successful engraftment and displayed clinical improvement, whereas untransplanted controls showed continuous weight loss and died. FAH immunohistochemistry

from livers of serial transplant recipients had extensive hepatocellular FAH staining, further demonstrating stability of the gene repair (Fig. Selleck Sorafenib 2A). AAV8 is the preferred serotype for liver transduction because of its strong hepatic tropism, rapid capsid disassembly and genome release.36 In contrast, although AAV2 has been shown to transduce liver, it is characterized by slow capsid disassembly and genome release. To address the question whether CDK inhibitor AAV serotypes 8 and 2 have different gene repair dynamics in vivo, d3 Fah5981SB neonates were treated

with 2 × 1011 vg of AAV8-Fah or 1 × 1011 vg of AAV2-Fah and analyzed after 1, 2, or 4 weeks post-treatment for the presence of FAH+ hepatocytes (Fig. 3). In AAV8-Fah treated mice, the highest number of FAH+ hepatocytes seen (up to 1/180 hepatocytes) were detected within the first week post-treatment. Correction frequencies declined with time and stabilized after 4 weeks. In contrast, AAV2-treated mice had little detectable Fah expression within the first seven days, supporting the fact that AAV2 uncoats more slowly than AAV8. Week two showed an increase in Fah expression that remained stable until week four. No FAH+ hepatocytes were detected at any time point in control mice injected with serotype-matched irrelevant control vectors AAV8-GFP or AAV2-hAAT at equivalent doses. These results conclusively demonstrate that emergence of FAH+ hepatocytes were neither due to spontaneous reversion, nor gene repair stimulated non-specifically by mere AAV transduction.

6A and Supporting Information). Substitutions p.L127P and p.G1040R are predicted to result in structural changes within the transmembrane domains of ATP8B1 (Fig. 6B,F). The p.G308V mutation causes a destabilizing rearrangement in the ATP8B1 Actuator domain (Fig. 6C), which likely influences the association between the Actuator this website and Phosphorylation domains (indicated by A and P in Fig. 6A), two ATP8B1 structural domains that are highly conserved in all P-type ATPases. The residues D454 and D554 are close together in the cytosolic core of the protein, and are critical for the catalytic cycle of P-type ATPases (Fig. 6D). I661

is a fully exposed residue, located in the Nucleotide-binding domain (N-domain) (Fig. 6E). The I661T mutation does not seem to result in major structural changes within ATP8B1, selleck chemical in line with the relatively mild clinical consequences of this mutation.11 ATP8B1 R1164X lacks three helical turns

of the last transmembrane helix (shown green in Fig. 6A) and 80 C-terminal residues, whose structure could not be reliably predicted. Together, these modeling data support the hypothesis that most of the studied mutations result in significant structural alterations. We investigated whether treatment with the pharmacological chaperone 4-PBA ameliorated the low expression of ATP8B1 mutants. ATP8B1 G308V protein expression was significantly increased by 4-PBA treatment in a dose-dependent manner (Fig. 7A). Total cellular expression of ATP8B1 G308V, D454G, D554N, and R1164X was induced two-fold to five-fold by 4-PBA treatment (Fig. 7B). Interestingly, protein expression of ATP8B1 I661T and G1040R showing

only mildly reduced expression levels in control conditions, also poorly responded to 4-PBA treatment. ATP8B1 WT expression was not stimulated by 4-PBA, suggesting specific up-regulation Interleukin-3 receptor of otherwise misfolded proteins. Subsequently, cell surface biotinylation was performed to determine whether 4-PBA stimulated the trafficking of ATP8B1 mutants to the cell surface. Neither ATP8B1 nor the transferrin receptor (used as a loading control) was detected when biotin was omitted, indicating the specificity of the signal for cell surface resident proteins. ATP8B1 G308V, D454G, and D554N showed a 1.5-fold to 2-fold increase in plasma membrane expression upon 4-PBA treatment (Fig. 8B). Despite increased protein expression upon 4-PBA treatment, no ATP8B1 R1164X signal was detectable at the cell surface in either condition. Interestingly, ATP8B1 I661T abundance in the biotinylated fraction was strongly enhanced (5-fold to 10-fold) upon 4-PBA treatment, suggesting markedly improved trafficking to the plasma membrane (Fig. 8A,B). The reverse occurred when cells were cultured at 40°C. This temperature increase resulted in a significant decrease in the amount of ATP8B1 I661T, but not WT protein at the cell surface (Fig. 8C).

Methods: Serum samples and clinical data of 78 subjects with acute DILI enrolled in DILIN obtained within 2 weeks of clinical onset were analyzed. Subjects were followed for 6 months or longer to determine outcome (recovery, death/liver Sunitinib transplant). miRNA profiles in serum were compared to those from 40 healthy controls. miR-NAs were isolated from 200 μL of serum and samples were hybridized to miRNA chip containing 1733 miRNAs and 1658 probes for pre-miRNAs. Descriptive statistics were compared using the Student’s t-test or analysis of variance (ANOVA), and univariate analyses were performed to compare those who died within 6 months

vs. those who survived. ANOVA with Benjamini-Hochberg false discovery rate correction was used and an adjusted p<0.05 was considered significant. Results: The mean age of the DILI cohort was 48 years-old, 55% were female and 78% Caucasian. 55% developed hepatocellular injury FK506 nmr and 22% cholestatic injury. 10 (12.8%) subjects died, 9 due to liver disease within 6 months of DILI onset. One died of non-DILI cause. Among 1733 miRNA’s analyzed 8 (122, 4532, 4484, 4463, 4270,1246, 4433, 4767) had elevated serum levels, while 3 (455-3p,

1281, 4274) decreased levels, (p<0.0001), in acute DILI cases compared to controls. 7 of the increased miRNAs were significantly correlated with ALT (p<0.01) (except 4532). miRNA-122 was increased the greatest [18-fold] [p = 10-11]. Among the 1733 miRNAs, 3 were associated with death within 6 months (miRNA−122,−

4463, −4270, P<0.05). None of the subjects with miRNA-122 greater than the median (8.31) died within 6 months. The combination of miRNA-122 serum level <7.89 and serum albumin <2.8 g/dL had sensitivity, specificity, PPV, NPV and accuracy of 100%, 81%, 38%, 100%, 83%, respectively. Conclusions: Acute DILI is associated with significant changes in a relatively small subset of serum miRNAs. The liver specific miRNA-122 combined with serum albumin levels accurately identified subjects who were likely to die within 6 months of DILI onset. If confirmed in other cohorts, serum levels of miRNA-122 and albumin, early in the course of disease, may be useful in identifying patients at greatest risk for mortality. Progesterone Disclosures: Mark W. Russo – Grant/Research Support: Merck; Speaking and Teaching: Gilead, Janssen, Salix, Bayer Naga P. Chalasani – Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aegerion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin Robert J. Fontana – Consulting: GlaxoSmithKline; Grant/Research Support: Gilead, vertex, BMS, Jansen Herbert L. Bonkovsky – Advisory Committees or Review Panels: Clinuvel, Inc., Novartis Pharmaceuticals, Clinuvel, Inc., Novartis Pharmaceuticals, Clinuvel, Inc., Novartis Pharmaceuticals, Clinuvel, Inc., Novartis Pharmaceuticals; Consulting: Alnylam, Inc, Clinuvel, Inc., Novartis Pharmaceuticals, Lundbeck Pharmaceuticals, Boehringer-Ingelheim, Clinuvel, Inc.