The role of osteopontin in liver fibrosis

150 p.Osteopontin (OPN) is a cytokine and matrix molecule that is upregulated in human and mouse models of chronic liver injury and directly promotes liver fibrogenesis by activating hepatic stellate cells (HSC) and liver progenitors (LPC). OPN is secreted by multiple cell types including HSC, LPC, as well as recruited immune cells such as natural killer T (NKT) cells, which amplify the fibrogenic response. In vivo, OPN neutralization abrogates the LPC response, inhibits HSC activation, and reduces liver fibrosis, thus demonstrating that targeting OPN is a potentially attractive anti-fibrotic strategy

NASH, Metabolic Syndrome, and Diabetes: How Sugar and Fat Increase the Risk of Developing Advanced Liver Disease

Open Access funding enabled and organized by Projekt DEAL

The role of osteopontin in liver fibrosis

150 p.Osteopontin (OPN) is a cytokine and matrix molecule that is upregulated in human and mouse models of chronic liver injury and directly promotes liver fibrogenesis by activating hepatic stellate cells (HSC) and liver progenitors (LPC). OPN is secreted by multiple cell types including HSC, LPC, as well as recruited immune cells such as natural killer T (NKT) cells, which amplify the fibrogenic response. In vivo, OPN neutralization abrogates the LPC response, inhibits HSC activation, and reduces liver fibrosis, thus demonstrating that targeting OPN is a potentially attractive anti-fibrotic strategy

Mechanisms for Vascular Cell Adhesion Molecule-1 Activation of ERK1/2 during Leukocyte Transendothelial Migration

Background: During inflammation, adhesion molecules regulate recruitment of leukocytes to inflamed tissues. It is reported that vascular cell adhesion molecule-1 (VCAM-1) activates extracellular regulated kinases 1 and 2 (ERK1/2), but the mechanism for this activation is not known. Pharmacological inhibitors of ERK1/2 partially inhibit leukocyte transendothelial migration in a multi-receptor system but it is not known whether VCAM-1 activation of ERK1/2 is required for leukocyte transendothelial migration (TEM) on VCAM-1. Methodology/Principal Findings: In this study, we identified a mechanism for VCAM-1 activation of ERK1/2 in human and mouse endothelial cells. VCAM-1 signaling, which occurs through endothelial cell NADPH oxidase, protein kinase Ca (PKCa), and protein tyrosine phosphatase 1B (PTP1B), activates endothelial cell ERK1/2. Inhibition of these signals blocked VCAM-1 activation of ERK1/2, indicating that ERK1/2 is activated downstream of PTP1B during VCAM-1 signaling. Furthermore, VCAM-1-specific leukocyte migration under physiological laminar flow of 2 dynes/cm 2 was blocked by pretreatment of endothelial cells with dominant-negative ERK2 K52R or the MEK/ERK inhibitors, PD98059 and U0126, indicating for the first time that ERK regulates VCAM-1-dependent leukocyte transendothelial migration. Conclusions/Significance: VCAM-1 activation of endothelial cell NADPH oxidase/PKCa/PTP1B induces transient ERK1/2 activation that is necessary for VCAM-1-dependent leukocyte TEM

Hepatokines and adipokines in NASH-related hepatocellular carcinoma

Summary The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non- alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD- related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, pre- ventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipo- kines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors – in particular, angiopoietin-like proteins, fi broblast growth factors, and apelin – for detection or even as therapeutic targets in NAFLD-related HCC.Supported by the German Research Foundation (DFG CA267/13-3; CA267/14-1) and the Wilhelm Laupitz Foundation (A.C. and O.K.)

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)-the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Sowa, Jan Peter. Ruhr Universität Bochum; AlemaniaFil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Kücükoglu, Özlem. Otto-von-Guericke-Universität Magdeburg; AlemaniaFil: Syn, Wing Kin. Universidad del País Vasco; España. Medical University of South Carolina; Estados Unidos. University of the Basque Country; EspañaFil: Canbay, Ali. Ruhr Universität Bochum; Alemani

The contribution of daytime sleepiness to impaired quality of life in NAFLD in an ethnically diverse population

Health-related quality of life (HRQoL) is lower in people with NAFLD compared to the general population. Sleep disturbance resulting in daytime sleepiness is common in patients with NAFLD, but the effect of daytime sleepiness on HRQoL in NAFLD is unclear. The prevalence and natural history of NAFLD vary in different ethnic groups, but there has been limited ethnic diversity in HrQoL studies to date. We aimed to assess whether daytime sleepiness is independently associated with reduced HRQoL in an ethnically diverse UK population. We conducted HRQoL assessments using SF-36 version 2 and Epworth Sleepiness Scale (ESS) questionnaires in 192 people with NAFLD. Multivariate linear regression was used to identify factors independently affecting HRQoL scales. People with NAFLD reported significantly reduced physical health-related SF-36 scores compared to the general UK population. South Asian NAFLD patients reported impairment in physical health, but not mental health, approximately a decade before White NAFLD patients. In multivariate linear regression, daytime sleepiness (ESS score > 10), was the most significant independent predictor of reduced physical health. Age, BMI and liver stiffness score were also significantly associated. HRQoL is impaired earlier in patients of South Asian ethnicity. ESS score > 10, indicative of excessive daytime sleepiness, is an independent predictor of reduced HRQoL in people with NAFLD regardless of ethnicity. Daytime sleepiness should be considered as a contributing factor to reduced HRQoL in clinical practice and when evaluating patient-related outcomes in clinical trials.Grant from the Diabetes Wellness and Research Foundation (WA, WKS). WA was supported by a New Investigator Research Grant from the Medical Research Council

Single-cell phenotypes of peripheral blood immune cells in early and late stages of non-alcoholic fatty liver disease

Background/Aims Immune and inflammatory cells respond to multiple pathological hits in the development of nonalcoholic steatohepatitis (NASH) and fibrosis. Relatively little is known about how their type and function change through the non-alcoholic fatty liver disease (NAFLD) spectrum. Here we used multi-dimensional mass cytometry and a tailored bioinformatic approach to study circulating immune cells sampled from healthy individuals and people with NAFLD. Methods Cytometry by time of flight using 36 metal-conjugated antibodies was applied to peripheral blood mononuclear cells (PBMCs) from biopsy-proven NASH fibrosis (late disease), steatosis (early disease), and healthy patients. Supervised and unsupervised analyses were used, findings confirmed, and mechanisms assessed using independent healthy and disease PBMC samples. Results Of 36 PBMC clusters, 21 changed between controls and disease samples. Significant differences were observed between diseases stages with changes in T cells and myeloid cells throughout disease and B cell changes in late stages. Semi-supervised gating and re-clustering showed that disease stages were associated with fewer monocytes with active signalling and more inactive NK cells; B and T cells bearing activation markers were reduced in late stages, while B cells bearing co-stimulatory molecules were increased. Functionally, disease states were associated with fewer activated mucosal-associated invariant T cells and reduced toll-like receptor-mediated cytokine production in late disease. Conclusions A range of innate and adaptive immune changes begin early in NAFLD, and disease stages are associated with a functionally less active phenotype compared to controls. Further study of the immune response in NAFLD spectrum may give insight into mechanisms of disease with potential clinical application

Atorvastatin Provides a New Lipidome Improving Early Regeneration After Partial Hepatectomy in Osteopontin Deficient Mice

Osteopontin (OPN), a multifunctional cytokine that controls liver glycerolipid metabolism, is involved in activation and proliferation of several liver cell types during regeneration, a condition of high metabolic demands. Here we investigated the role of OPN in modulating the liver lipidome during regeneration after partial-hepatectomy (PH) and the impact that atorvastatin treatment has over regeneration in OPN knockout (KO) mice. The results showed that OPN deficiency leads to remodeling of phosphatidylcholine and triacylglycerol (TG) species primarily during the first 24 h after PH, with minimal effects on regeneration. Changes in the quiescent liver lipidome in OPN-KO mice included TG enrichment with linoleic acid and were associated with higher lysosome TG-hydrolase activity that maintained 24 h after PH but increased in WT mice. OPN-KO mice showed increased beta-oxidation 24 h after PH with less body weight loss. In OPN-KO mice, atorvastatin treatment induced changes in the lipidome 24 h after PH and improved liver regeneration while no effect was observed 48 h post-PH. These results suggest that increased dietary-lipid uptake in OPN-KO mice provides the metabolic precursors required for regeneration 24 h and 48 h after PH. However, atorvastatin treatment offers a new metabolic program that improves early regeneration when OPN is deficient.This work was supported by IT-336-10 (Gobierno Vasco) (to PA) and SAF2015-64352-R (to PA), SAF2017-87301-R (to MLM-C) and EITB Maratoia BIO15/CA/014 (to MLM-C). MNG and DM were recipients of a predoctoral fellowship from the University of Basque Country UPV/EHU and BG-S and DS were recipients for predoctoral fellowships from the Basque Goverment. We thank technical support from Jose Antonio Lopez Gomez