Multicellular liver organoid model for recapitulating hepatitis C virus infection and non-alcoholic fatty liver disease progression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229609 | GEO | 2024/05/05
REPOSITORIES: GEO
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Project description:Hepatitis C virus (HCV) infection has been successfully managed by anti-viral therapies, however, high prevalence to severe chronic liver disease state including non-alcoholic fatty liver disease (NAFLD) is a problem encountered even after the cure of hepatitis C. Moreover, there is currently no reliable in vitro model capable of investigating host-viral interactions and monitoring the progression of viral hepatitis to chronic liver diseases. Recent organoid technology has been reported for successful infection of HCV, but there is still lack of non-parenchymal cells, which play a crucial role in disease progression. Here, we provided a novel multicellular liver organoid model using co-culture system of macrophages and liver organoids differentiated from the same cell source, human embryonic stem cells. Surprisingly, HCV infection led potent lipid accumulation in liver organoids through regulation of host lipid metabolism, which was further promoted by macrophage co-culture. Lipid enriched condition provided by longterm-treatment with fatty acid accelerated potent HCV amplification and further promotion of inflammation and fibrosis progression. Therefore, our model may be a valuable novel platform recapitulating diverse phenotypes with host-virus intercommunication and inter-cellular interactions and further progressive features of hepatitis C-associated chronic NAFLD progression of patients with HCV.
2024-05-05 | GSE229608 | GEO
Project description:Hepatitis C virus (HCV) infection has been successfully managed by anti-viral therapies, however, high prevalence to severe chronic liver disease state including non-alcoholic fatty liver disease (NAFLD) is a problem encountered even after the cure of hepatitis C. Moreover, there is currently no reliable in vitro model capable of investigating host-viral interactions and monitoring the progression of viral hepatitis to chronic liver diseases. Recent organoid technology has been reported for successful infection of HCV, but there is still lack of non-parenchymal cells, which play a crucial role in disease progression. Here, we provided a novel multicellular liver organoid model using co-culture system of macrophages and liver organoids differentiated from the same cell source, human embryonic stem cells. Surprisingly, HCV infection led potent lipid accumulation in liver organoids through regulation of host lipid metabolism, which was further promoted by macrophage co-culture. Lipid enriched condition provided by longterm-treatment with fatty acid accelerated potent HCV amplification and further promotion of inflammation and fibrosis progression. Therefore, our model may be a valuable novel platform recapitulating diverse phenotypes with host-virus intercommunication and inter-cellular interactions and further progressive features of hepatitis C-associated chronic NAFLD progression of patients with HCV.
2024-05-05 | GSE229596 | GEO
Project description:Hepatitis B virus (HBV) infection is a prevalent infectious disease with serious outcomes like chronic and acute hepatitis, cirrhosis, and hepatocellular carcinoma. However, the metabolic alteration by HBV is rarely taken into consideration. With the high prevalence of alcohol consumption and chronic HBV infection, their overlap is assumed to be an increasing latent hazard; although the extent has not been calculated. Moreover, the impact of chronic alcohol consumption combined with HBV on cholesterol metabolism is unknown. Six-week-old male FVB/Ncrl mice were hydrodynamically injected with a pGEM-4Z-1.3HBV vector and then fed an ethanol diet for 6 weeks. Serum biomarkers and liver histology, liver cholesterol levels, and cholesterol metabolism-related molecules were measured. In vitro assays with HBx, hepatitis B surface (HBs), or hepatitis B core (HBc) protein expression in HepG2 cells costimulated with ethanol were conducted to assess the cholesterol metabolism. HBV expression synergistically increased cholesterol deposition in the setting of alcoholic fatty liver. The increase of intrahepatic cholesterol was due to metabolic alteration in cholesterol metabolism, including increased cholesterol synthesis, decreased cholesterol degradation, and impaired cholesterol uptake. Overexpression of HBV component HBc, but not HBs or HBx, selectively promoted the hepatocellular cholesterol level.
| S-EPMC5748497 | biostudies-literature
Project description:Knowing the rate of liver fibrosis progression in hepatitis C virus (HCV)-infected persons can help inform patients and providers (clinicians, medical institutions or organizations, and third-party payers) in making treatment decisions.To determine the rate and factors associated with liver fibrosis progression and hepatic decompensation in persons after acquiring HCV infection.Secondary data analysis of persons in the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a national Veterans Affairs (VA) database, between 2002 and 2012. Among 610?514 persons in ERCHIVES (half were HCV positive), we identified those with an initial negative and subsequent positive test result for HCV antibody and positive HCV RNA test result (HCV+). Controls had 2 negative HCV antibody test results (HCV-) in a comparable time frame and were matched 1:1 on age (in 5-year blocks), race, and sex. We excluded persons with human immunodeficiency virus, hepatitis B, less than 24 months of follow-up, hepatocellular carcinoma, and cirrhosis at baseline.Progression of liver fibrosis as estimated by the Fibrosis-4 (FIB-4) index; development of cirrhosis, defined by a FIB-4 score greater than 3.5; and development of hepatic decompensation.The evaluable data set consisted of 1840 persons who were HCV+ and 1840 HCV- controls. The HCV+ persons were younger and had a lower mean (SD) body mass index (27.39 [5.51] vs 29.49 [6.16]; P?<?.001), a higher prevalence of alcohol and drug abuse and dependence diagnoses, and higher serum aminotransferase levels, but had a lower prevalence of diabetes and hypertension. Fibrosis progression started early after infection among HCV+ persons and tapered off after 5 years. A total of 452 cirrhosis and 85 hepatic decompensation events were recorded. After 10 years of follow-up, HCV+ persons were more likely to have a diagnosis of cirrhosis compared with HCV- controls (18.4% vs 6.1%). Nine years after diagnosis of cirrhosis, hepatic decompensation events were uncommon but had a higher rate in the HCV+ group (1.79% vs 0.33%).Persons who seroconverted for HCV have a more rapid progression of liver fibrosis and accelerated time to development of cirrhosis after seroconversion compared with HCV- controls. Fibrosis progression occurs early after infection; however, hepatic decompensation is uncommon after diagnosis of cirrhosis.
| S-EPMC5017246 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are currently the two most common liver diseases in the world. Alcoholic hepatitis (AH), a unique clinical syndrome among ALD patients has high short-term mortality. Apart from controlling the risk factor for individual respective disease, there are no Food and Drug Administration (FDA) approved medical therapies for these diseases. Over the last 5-10 years, the field has extensively grown with many new targets being studied in randomized clinical trials for these diseases, with many of these drugs being tested in both the conditions. In this chapter, we will describe the novel therapeutic agents and current status of ongoing clinical trials with these agents for the treatment of NAFLD and/or AH.
| S-EPMC6691078 | biostudies-literature
Project description:Background and aimThe incidence of non-alcoholic fatty liver disease (NAFLD) is increasing all over the world. NAFLD develops in patients with liver disease, including patients with autoimmune hepatitis (AIH). NAFLD and AIH have some similar laboratory and histological findings. The aim of this study was to elucidate the characteristics of AIH patients with NAFLD.MethodsWe re-evaluated the nationwide survey performed in Japan in 2015 of AIH patients diagnosed between 2009 and 2013.ResultsA total of 1151 subjects (144 men and 1007 women) were enrolled in the present study. The overall prevalence of NAFLD was 17.0%. Compared to AIH without NAFLD, AIH patients with NAFLD had the following characteristics: (i) low female-to-male ratio, (ii) older age, (iii) mild elevation in hepatobiliary enzymes, (iv) histologically progressive fibrosis and mild plasma cell infiltration or mild lobular hepatitis, (v) lower prevalence of prednisolone administration and higher prevalence of ursodeoxycholic acid administration, (vi) higher levels of hepatic enzymes and immunoglobulin G after treatment, and (vii) similar prevalence of autoimmune and malignant complications.ConclusionAIH patients with NAFLD have many features that are different from AIH patients without NAFLD. Understanding these differences is essential for the proper diagnosis and treatment of AIH patients with NAFLD.
| S-EPMC6207019 | biostudies-literature
Project description:BACKGROUND: Chronic infection with hepatitis C virus (HCV) is a risk factor for liver diseases such as fibrosis, cirrhosis and hepatocellular carcinoma. HCV genetic heterogeneity was hypothesized to be associated with severity of liver disease. However, no reliable viral markers predicting disease severity have been identified. Here, we report the utility of sequences from 3 HCV 1b genomic regions, Core, NS3 and NS5b, to identify viral genetic markers associated with fast and slow rate of fibrosis progression (RFP) among patients with and without liver transplantation (n = 42). METHODS: A correlation-based feature selection (CFS) method was used to detect and identify RFP-relevant viral markers. Machine-learning techniques, linear projection (LP) and Bayesian Networks (BN), were used to assess and identify associations between the HCV sequences and RFP. RESULTS: Both clustering of HCV sequences in LP graphs using physicochemical properties of nucleotides and BN analysis using polymorphic sites showed similarities among HCV variants sampled from patients with a similar RFP, while distinct HCV genetic properties were found associated with fast or slow RFP. Several RFP-relevant HCV sites were identified. Computational models parameterized using the identified sites accurately associated HCV strains with RFP in 70/30 split cross-validation (90-95% accuracy) and in validation tests (85-90% accuracy). Validation tests of the models constructed for patients with or without liver transplantation suggest that the RFP-relevant genetic markers identified in the HCV Core, NS3 and NS5b genomic regions may be useful for the prediction of RFP regardless of transplant status of patients. CONCLUSIONS: The apparent strong genetic association to RFP suggests that HCV genetic heterogeneity has a quantifiable effect on severity of liver disease, thus presenting opportunity for developing genetic assays for measuring virulence of HCV strains in clinical and public health settings.
| S-EPMC4120150 | biostudies-literature
Project description:The complement system is a key component of the body's immune system. When abnormally activated, this system can induce inflammation and damage to normal tissues and participate in the development and progression of a variety of diseases. In the past, many scholars believed that alcoholic liver disease (ALD) is induced by the stress of ethanol on liver cells, including oxidative stress and dysfunction of mitochondria and protease bodies, causing hepatocyte injury and apoptosis. Recent studies have shown that complement activation is also involved in the genesis and development of ALD. This review focuses on the roles of complement activation in ALD and of therapeutic intervention in complement-activation pathways. We intend to provide new ideas on the diagnosis and treatment of ALD.
| S-EPMC6206158 | biostudies-other
Project description:During the progression from hepatitis to fibrosis, cirrhosis, and liver failure, the accumulation of stressed/damaged hepatocyte elements associated with liver inflammation is critical. The causes of hepatocyte injuries include viral hepatitis infections, alcoholic hepatitis, and non-alcoholic fatty liver disease. Hepatocyte-derived extracellular vesicles (Hep-EVs) released from stressed/damaged hepatocytes are partly responsible for liver disease progression and liver damage because they activate non-parenchymal cells and infiltrate inflammatory cells within the liver, which are in turn are an important source of EVs. This cell-to-cell signaling is prevalent during inflammation in many liver diseases. Accordingly, special emphasis should be placed on liquid biopsy methods for the long-term monitoring of chronic liver diseases. In the present review, we have highlighted various aspects of current liquid biopsy research into chronic liver diseases. We have also reviewed recent progress on liquid biopsies that focus on cell-free DNA (cfDNA), long non-coding RNA (lncRNA), and the proteins in EVs as potential diagnostic tools and novel therapeutic targets in patients with viral hepatitis, fatty liver steatosis, and alcoholic liver diseases.
| S-EPMC7279404 | biostudies-literature
Project description:At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a "wound healing" process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.
| S-EPMC6962431 | biostudies-literature