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Hypoxia-inducible factor 2α drives nonalcoholic fatty liver progression by triggering hepatocyte... Hypoxia-inducible factor 2α drives nonalcoholic fatty liver progression by triggering hepatocyte...

Date added: 02/13/2019
Date modified: 02/13/2019
Filesize: 256 Bytes
Downloads: 44

"Hypoxia-inducible factor 2α drives nonalcoholic fatty liver progression by triggering hepatocyte release of histidine rich glycoprotein"

Mechanisms underlying progression of nonalcoholic fatty liver disease (NAFLD) are still incompletely characterized. Hypoxia and hypoxia‐inducible factors (HIFs) have been implicated in the pathogenesis of chronic liver diseases, but the actual role of HIF‐2α in the evolution of NAFLD has never been investigated in detail. In this study, we show that HIF‐2α is selectively overexpressed in the cytosol and the nuclei of hepatocytes in a very high percentage (>90%) of liver biopsies from a cohort of NAFLD patients at different stages of the disease evolution. Similar features were also observed in mice with steatohepatitis induced by feeding a methionine/choline‐deficient diet. Experiments performed in mice carrying hepatocyte‐specific deletion of HIF‐2α and related control littermates fed either a choline‐deficient L‐amino acid–defined or a methionine/choline‐deficient diet showed that HIF‐2α deletion ameliorated the evolution of NAFLD by decreasing parenchymal injury, fatty liver, lobular inflammation, and the development of liver fibrosis. The improvement in NAFLD progression in HIF‐2α‐deficient mice was related to a selective down‐regulation in the hepatocyte production of histidine‐rich glycoprotein (HRGP), recently proposed to sustain macrophage M1 polarization. In vitro experiments confirmed that the up‐regulation of hepatocyte HRGP expression was hypoxia‐dependent and HIF‐2α‐dependent. Finally, analyses performed on specimens from NAFLD patients indicated that HRGP was overexpressed in all patients showing hepatocyte nuclear staining for HIF‐2α and revealed a significant positive correlation between HIF‐2α and HRGP liver transcript levels in these patients. Conclusions: These results indicate that hepatocyte HIF‐2α activation is a key feature in both human and experimental NAFLD and significantly contributes to the disease progression through the up‐regulation of HRGP production.

Liver fibrosis: Direct antifibrotic agents and targeted therapies Liver fibrosis: Direct antifibrotic agents and targeted therapies

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Date added: 12/31/2018
Date modified: 12/31/2018
Filesize: 256 Bytes
Downloads: 109

Liver fibrosis and in particular cirrhosis are the major causes of morbidity and mortality of patients with chronic liver disease. Their prevention or reversal have become major endpoints in clinical trials with novel liver specific drugs. Remarkable progress has been made with therapies that efficiently address the cause of the underlying liver disease, as in chronic hepatitis B and C. Highly effective antiviral therapy can prevent progression or even induce reversal in the majority of patients, but such treatment remains elusive for the majority of liver patients with advanced alcoholic or nonalcoholic steatohepatitis, genetic or autoimmune liver diseases. Moreover, drugs that would speed up fibrosis reversal are needed for patients with cirrhosis, since even with effective causal therapy reversal is slow or the disease may further progress. Therefore, highly efficient and specific antifibrotic agents are needed that can address advanced fibrosis, i.e., the detrimental downstream result of all chronic liver diseases. This review discusses targeted antifibrotic therapies that address molecules and mechanisms that are central to fibrogenesis or fibrolysis, including strategies that allow targeting of activated hepatic stellate cells and myofibroblasts and other fibrogenic effector cells. Focus is on collagen synthesis, integrins and cells and mechanisms specific including specific downregulation of TGFbeta signaling, major extracellular matrix (ECM) components, ECM-crosslinking, and ECM-receptors such as integrins and discoidin domain receptors, ECM-crosslinking and methods for targeted delivery of small interfering RNA, antisense oligonucleotides and small molecules to increase potency and reduce side effects. With an increased understanding of the biology of the ECM and liver fibrosis and an improved preclinical validation, the translation of these approaches to the clinic is currently ongoing. Application to patients with liver fibrosis and a personalized treatment is tightly linked to the development of non-invasive biomarkers of fibrosis, fibrogenesis and fibrolysis.

Determinants of fibrosis progression and regression in NASH Determinants of fibrosis progression and regression in NASH

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Date added: 11/02/2018
Date modified: 11/02/2018
Filesize: 256 Bytes
Downloads: 180

Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). However, progression to cirrhosis is less predictable in NASH than in other chronic liver diseases. This is due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with precirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis progression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detection, stratification and follow-up of patients with progressive NASH . These non-invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-ofconcept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease.

The bidirectional impacts of alcohol consumption and the metabolic syndrome: cofactors for prog... The bidirectional impacts of alcohol consumption and the metabolic syndrome: cofactors for prog...

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Date added: 11/02/2018
Date modified: 11/02/2018
Filesize: 256 Bytes
Downloads: 163

"The bidirectional impacts of alcohol consumption and the metabolic syndrome: cofactors for progressive fatty liver disease"

Current medical practice artificially dichotomises a diagnosis of fatty liver disease into one of two common forms: alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Together, these account for the majority of chronic liver diseases worldwide. In recent years, there has been a dramatic increase in the prevalence of obesity and metabolic syndrome within the general population. These factors now coexist with alcohol consumption in a substantial proportion of the population. Each exposure sensitises the liver to the injurious effects of the other; an interaction that drives and potentially accelerates the genesis of liver disease. We review the epidemiological evidence and scientific literature that considers how alcohol consumption interacts with components of the metabolic syndrome to exert synergistic or supra-additive effects on the development and progression of liver disease, before discussing how these interactions may be addressed in clinical practice.

Should we undertake surveillance for HCC in patients with NAFLD? Should we undertake surveillance for HCC in patients with NAFLD?

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Date added: 11/02/2018
Date modified: 11/02/2018
Filesize: 256 Bytes
Downloads: 172

The pandemic of obesity and its related complications is rapidly changing the epidemiology of many types of cancer, including hepatocellular carcinoma (HCC). Non-alcoholic fatty liver disease (NAFLD) is becoming a major cause of HCC, with a steadily rising trend compared to viral or alcohol-induced chronic hepatitis. The much greater prevalence of the underlying liver disease in the general population and the chance of HCC occurrence in non-cirrhotic liver are the most worrisome aspects of HCC in NAFLD. Effective screening programmes are currently hampered by limited knowledge of the pathways of carcinogenesis and a lack of tools able to stratify the risk of HCC in the NAFLD population. Hence, poor surveillance has prevented the development of an adequate treatment for NAFLD-related HCC. Systemic and hepatic molecular mechanisms involved in hepatocarcinogenesis, as well as potential early markers of HCC are being extensively investigated. This review describes the current clinical impact of HCC in NAFLD and discusses the most important unmet needs for its effective management.

Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention

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Date added: 11/01/2018
Date modified: 11/01/2018
Filesize: 256 Bytes
Downloads: 176

NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers.

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

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Date added: 11/01/2018
Date modified: 11/01/2018
Filesize: 256 Bytes
Downloads: 161

Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography–mass
spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR 5 endogenous glucose production 3 insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/[serine 1 glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R 5 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort.

Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index.

Inflammation induced IgA+ cells dismantle anti-liver cancer immunity Inflammation induced IgA+ cells dismantle anti-liver cancer immunity

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Date added: 08/07/2018
Date modified: 08/07/2018
Filesize: 256 Bytes
Downloads: 273

The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.

Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) – an 11-Year... Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) – an 11-Year...

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Date added: 08/07/2018
Date modified: 08/07/2018
Filesize: 1.38 MB
Downloads: 182

"Predictors of Liver Fat and Stiffness in Non-Alcoholic Fatty Liver Disease (NAFLD) – an 11-Year Prospective Study"

Liver fat can be non-invasively measured by proton magnetic resonance spectroscopy (1H-MRS) and fibrosis estimated as stiffness using transient elastography (FibroScan). There are no longitudinal data on changes in liver fat in Europids or on predictors of liver stiffness using these methods. We determined liver fat (1H-MRS) and clinical characteristics including features of insulin resistance at baseline and after a median follow-up period of 11.3 (range 7.3–13.4) years in 97 Finnish subjects. Liver stiffness was measured at 11.3 years. Liver fat content decreased by 5% (p < 0.05) over time. Values at baseline and 11.3 years were closely interrelated (r = 0.81, p < 0.001). Baseline liver fat (OR 1.32; 95%CI: 1.15–1.50) and change in BMI (OR 1.67; 95%CI: 1.24–2.25) were independent predictors of liver fat at 11.3 years (AUROC 0.90; 95%CI: 0.83–0.96). Baseline liver fat (AUROC 0.84; 95%CI: 0.76–0.92) predicted liver fat at 11.3 years more accurately than routinely available parameters (AUROC 0.76; 95%CI: 0.65–0.86, p = 0.02). At 11.3 years, 29% of the subjects had increased liver stiffness. Baseline liver fat (OR 2.17; 95%CI: 1.05–4.46) was an independent predictor of increased liver stiffness. These data show that liver fat is more important than the associated metabolic abnormalities as the predictor of future liver fat and fibrosis.

Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD? Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD?

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Date added: 08/07/2018
Date modified: 08/07/2018
Filesize: 256 Bytes
Downloads: 294

Whether non-alcoholic fatty liver disease (NAFLD) precedes insulin resistance (IR) or IR preludes/causes NAFLD has been long debated. Recent studies have shown that there are two phenotypes of NAFLD, ‘genetic’ vs ‘metabolic’ NAFLD. The former patients are more at risk of hepatocellular carcinoma and chronic liver disease the latter are more IR and at increased risk of type 2 diabetes (T2D). Even if they are not yet diabetics, from a metabolic point of view having NAFLD is equivalent to T2D with reduced peripheral glucose disposal and impaired suppression of hepatic glucose production, but without fasting hyperglycaemia. T2D develops only when hepatic autoregulation is lost and glucose production exceeds the capacity of muscle glucose disposal.

In NAFLD adipocytes are resistant to the effect of insulin, lipolysis is increased and excess plasma free fatty acids (FFA) are taken up by other organs (mainly liver) where they are stored as lipid droplets or oxidized. Increased adiposity is associated with worsen severity of both ‘genetic’ and ‘metabolic’ NAFLD. FFA oxidative metabolism is increased in NAFLD and not shifted towards glucose during insulin infusion. Although this reduced metabolic flexibility is an early predictor of T2D, it can be seen also as a protective mechanism against excess FFA.

In conclusion, IR precedes and causes ‘metabolic’ NAFLD, but not ‘genetic’ NAFLD. Reduced metabolic flexibility in NAFLD might be seen as a protective mechanism against FFA overflow, but together with IR remains a strong risk factor for T2D that develops with the worsening of hepatic regulation of glucose production.