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Background & Aims: A number of genetic polymorphisms have been associated with susceptibility to or protection against non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409 C>G single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD., Methods: To enable mechanistic dissection, we developed a human pluripotent stem cell (hPSC)-derived multicellular liver culture by incorporating hPSC-derived hepatocytes, hepatic stellate cells, and macrophages. We first applied this liver culture to model NAFLD by utilising a lipotoxic milieu reflecting the circulating levels of disease risk factors in affected individuals. We then created an isogenic pair of liver cultures differing only at rs738049 and compared NAFLD phenotype development., Results: Our hPSC-derived liver culture recapitulated many key characteristics of NAFLD development and progression including lipid accumulation and oxidative stress, inflammatory response, and stellate cell activation. Under the lipotoxic conditions, the I148M variant caused the enhanced development of NAFLD phenotypes. These differences were associated with elevated IL-6/signal transducer and activator of transcription 3 (STAT3) activity in liver cultures, consistent with transcriptomic data of liver biopsies from individuals carrying the rs738409 SNP. Dampening IL-6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, whereas boosting it in wild-type liver cultures enhanced NAFLD development. Finally, we attributed this elevated IL-6/STAT3 activity in liver cultures carrying the rs738409 SNP to increased NF-κB activity., Conclusions: Our study thus reveals a potential causal link between elevated IL-6/STAT3 activity and 148M-mediated susceptibility to NAFLD., Impact and Implications: An increasing number of genetic variants manifest in non-alcoholic fatty liver disease (NAFLD) development and progression; however, the underlying mechanisms remain elusive. To study these variants in human-relevant systems, we developed an induced pluripotent stem cell-derived multicellular liver culture and focused on a common genetic variant (i.e. rs738409 in PNPLA3). Our findings not only provide mechanistic insight, but also a potential therapeutic strategy for NAFLD driven by this genetic variant in PNPLA3. Our liver culture is therefore a useful platform for exploring genetic variants in NAFLD development., Competing Interests: Conflicts of interest CMR is a founder of Apath LLC; a Scientific Advisory Board member of Imvaq Therapeutics, Vir Biotechnology, and Arbutus Biopharma; and an advisor for Regulus Therapeutics and Pfizer. CEM is a cofounder of Onegevity. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: To determine the prevalence of moderate-to-severe hepatic steatosis (HS) and associated risk factors in members of the World Trade Center (WTC) General Responder Cohort (GRC) who qualify for low-dose non-contrast computed tomography for lung cancer screening and compare them to non-WTC participants in the same screening program., Methods: All participants gave written informed consent before participating in this IRB-approved study. Clinical variables and laboratory values were recorded. Hepatic attenuation measurement (Hounsfield unit; HU) was measured on low-dose computed tomography (LDCT) and a threshold attenuation value <40HU indicated moderate-to-severe HS. Bivariate and multivariable linear and logistic regression analyses were performed. Propensity scores (PS) were calculated and inverse probability weighting (IPW) was used to adjust for potential confounders when comparing the WTC with non-WTC participants., Results: The prevalence of moderate-to-severe HS was 16.2% among 154 WTC participants compared to 5.3% among 170 non-WTC participants. In WTC members, moderate-to-severe HS was associated with higher BMI, higher laboratory liver function tests, and former smoking status. Using PS analysis and IPW to account for potential confounders, the odds ratio for moderate-to-severe HS was 3.4-fold higher (95% confidence interval: 1.7-6.7) in the WTC participants compared with non-WTC participants. Moderate-to-severe HS was also associated with higher BMI and former smoker status., Conclusion: Prevalence of moderate-to-severe HS was >3-fold higher in the WTC-GRC group than in other participants., Competing Interests: Declaration of competing interest Dr. Yankelevitz is a named inventor on a number of patents and patent applications relating to the evaluation of diseases of the chest including measurement of nodules. Some of these, which are owned by Cornell Research Foundation (CRF), are non-exclusively licensed to General Electric. As an inventor of these patents, Dr. Yankelevitz is entitled to a share of any compensation which CRF may receive from its commercialization of these patents. He is also an equity owner in Accumetra, a privately held technology company committed to improving the science and practice of image-based decision making (7 Corporate Drive, Clifton Park, NY 12065; Tel: 518–280-7530; http://accumetra.com/). Dr. Yankelevitz also serves on the advisory board of GRAIL (1525 O'Brien Drive, Menlo Park, CA 94025; Tel: 650–542-0372; https://grail.com/). Dr. Henschke is the President and serves on the board of the Early Diagnosis and Treatment Research Foundation. She receives no compensation from the Foundation. The Foundation is established to provide grants for projects, conferences, and public databases for research on early diagnosis and treatment of diseases. Dr. Claudia Henschke is also a named inventor on a number of patents and patent applications relating to the evaluation of pulmonary nodules on CT scans of the chest which are owned by Cornell Research Foundation (CRF). Since 2009, Dr. Henschke does not accept any financial benefit from these patents including royalties and any other proceeds related to the patents or patent applications owned by CRF. Other authors declare no conflicts of interest., (Copyright © 2019. Published by Elsevier Inc.)

Background & Aims: Although patients infected by genotype 1b hepatitis C virus (HCV) with Q(70) and/or M(91)core gene mutations have an almost five-fold increased risk of developing hepatocellular carcinoma (HCC) and increased insulin resistance, the absence of a suitable experimental system has precluded direct experimentation on the effects of these mutations on cellular gene expression., Methods: HuH7 cells were treated long-term with human serum to induce differentiation and to produce a model system for testing high-risk and control HCV. For clinical validation, profiles of infected cells were compared to each other and to those of liver biopsies of patients with early-stage HCV-related cirrhosis followed prospectively for up to 23 years (n=216)., Results: Long-term culture in human serum produced growth-arrested, hepatocyte-like cells whose gene profile overlapped significantly with that of primary human hepatocytes. High-risk (Q(70)/M(91)) and control (R(70)/L(91)) viruses had dramatically different effects on gene expression of these cells. The high-risk virus enhanced expression of pathways associated with cancer and type II diabetes, while the control virus enhanced pathways associated with oxidative phosphorylation. Of special clinical relevance, the transcriptome of cells replicating the high-risk virus correlated significantly with an HCC high-risk profile in patients (Bonferroni-corrected p=0.03), whereas no such association was observed for non-HCC-related clinical outcomes., Conclusions: The cell-based system allowed direct head-to-head comparison of HCV variants, and provided experimental support for previous clinical data indicating an oncogenic effect of core gene mutations. This simple experimental system distinguished HCV variants and will enable future mechanistic analysis and exploration of interventional approaches., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Among patients with hepatitis C virus (HCV) monoinfection, 25-hydroxyvitamin D [25(OH)D] concentrations are positively associated with a response to peg-interferon/ribavirin. Data on the relation between 25(OH)D concentrations and HCV treatment response in HIV-infected patients are limited., Objective: The objective was to determine whether baseline 25(OH)D concentrations predict virologic response in HIV/HCV co-infected patients and to examine variables associated with 25(OH)D concentrations ≥30 ng/mL., Design: Data and samples from 144 HCV genotype 1, treatment-naive patients from a completed HCV treatment trial were examined in this retrospective study. Early virologic response (EVR) was defined as ≥2 log10 reduction in HCV RNA and/or HCV RNA <600 IU/mL at week 12 of peg-interferon/ribavirin treatment. Baseline 25(OH)D was measured by liquid chromatography/tandem mass spectrometry., Results: Compared with the non-EVR control group (n = 68), the EVR group (n = 76) was younger, had fewer cirrhotic subjects, had a higher proportion with the IL28B CC genotype, had a higher albumin concentration, and had a lower HCV viral load at baseline (P ≤ 0.05). The difference in baseline 25(OH)D concentrations between EVR and non-EVR patients was not statistically significant (median: 25 ng/mL compared with 20 ng/mL; P = 0.23). Similar results were found for sustained virologic response (SVR). In multivariable analysis, white and Hispanic race-ethnicity (OR: 6.26; 95% CI: 2.47, 15.88; P = 0.0001) and ritonavir use (OR: 2.68; 95% CI: 1.08, 6.65; P = 0.033) were associated with higher 25(OH)D concentrations (≥30 ng/mL)., Conclusion: Baseline 25(OH)D concentrations did not predict EVR or SVR. Because ritonavir impairs the conversion of 25(OH)D to the active metabolite, utilization of 25(OH)D may have been impaired in subjects taking ritonavir. This trial was registered at www.clinicaltrials.gov as NCT00078403.

Vitamin D is increasingly becoming recognized as an important physiological regulator with pleiotropic functions outside of its classical role in skeletal homeostasis. A growing body of clinical evidence highlights the prevalence and risks of vitamin D deficiency in patients suffering from chronic hepatitis C infection, and vitamin D supplementation has been proposed as an adjunct to current standards of care. This review considers the experimental evidence for the anti-inflammatory, antifibrotic and antiviral effects of vitamin D, and discusses the therapeutic potential of vitamin D supplementation to protect against liver disease progression and improve responses to treatment., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology., Methods: This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48 weeks. Serum HCV RNA was measured 24 weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR >2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined., Results: Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR < 2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2-4, and 7% (3/41) of those with HOMA-IR > 4 (p = 0.01). In multivariable analysis, insulin resistance and log₁₀ HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05-0.64, p = 0.009, and AOR 0.36; 95% CI 0.14-0.93, p = 0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p = 0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes., Conclusions: In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Gene expression profiling allows the level of activity of thousands of genes to be monitored simultaneously. Profiling is often carried out on specialized chips or slides, which have microarrays of gene targets at predetermined addresses. In the immediate future, microarrays promise to yield new insights into hepatitis C virus (HCV) pathogenesis and to produce 'signatures' that can be used in molecular diagnostics. In the longer-term, they may aid the development of serological tests by identifying genes encoding secretory proteins produced by HCV-infected livers, and they may suggest new avenues for disease intervention by detecting genes whose products are retained in the infected liver.