Link to publication on Research at Birmingham portal General rightsUnless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. The express permission of the copyright holder must be obtained for any use of this material other than for purposes permitted by law.• Users may freely distribute the URL that is used to identify this publication.• Users may download and/or print one copy of the publication from the University of Birmingham research portal for the purpose of private study or non-commercial research.• User may use extracts from the document in line with the concept of 'fair dealing' under the Copyright, Designs and Patents Act 1988 (?) • Users may not further distribute the material nor use it for the purposes of commercial gain.Where a licence is displayed above, please note the terms and conditions of the licence govern your use of this document.When citing, please reference the published version. Take down policyWhile the University of Birmingham exercises care and attention in making items available there are rare occasions when an item has been uploaded in error or has been deemed to be commercially or otherwise sensitive.

Over the past 2 decades, nonalcoholic fatty liver disease (NAFLD) has grown from a relatively unknown disease to the most common cause of CLD in the world. In fact, 25% of the world's population is currently thought to have NAFLD. Non-alcoholic steatohepatitis (NASH) is the subtype of NAFLD that can progress to cirrhosis, hepatocellular carcinoma, and death. NAFLD and NASH are found in not only adults-there is a high prevalence in children and adolescents. Due to NAFLD's close association with type 2 diabetes (T2DM) and obesity, the latest models predict the prevalence of NAFLD and NASH will increase, causing a tremendous clinical and economic burden and poor patient-reported outcomes. Nonetheless, there is no accurate non-invasive method to detect NASH and treatment is limited to life style modifications. To examine the state of NAFLD among different regions and understand the global trajectory of this disease, an international group of experts came together during 2017 AASLD Global NAFLD Forum. We provide a summary of this forum and an assessment of the current state of NAFLD and NASH worldwide. This article is protected by copyright. All rights reserved.

Nonalcoholic steatohepatitis (NASH) is considered the progressive form of nonalcoholic fatty liver disease (NAFLD) and is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. A central issue in this field relates to the identification of those factors that trigger inflammation, thus fuelling the transition from nonalcoholic fatty liver to NASH. These triggers of liver inflammation might have their origins outside the liver (such as in adipose tissue or the gut) as well as inside the organ (for instance, lipotoxicity, innate immune responses, cell death pathways, mitochondrial dysfunction and endoplasmic reticulum stress), both of which contribute to NASH development. In this Review, we summarize the currently available information on the key upstream triggers of inflammation in NASH. We further delineate the mechanisms by which liver inflammation is resolved and the implications of a defective pro-resolution process. A better knowledge of these mechanisms should help to design targeted therapies able to halt or reverse disease progression.

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium‐dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile‐acid‐related pathways to address this growing world‐wide disease. (Hepatology 2017;65:350‐362)

No abstract

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches based on a profound understanding of its pathogenesis to halt disease progression to advanced fibrosis or cirrhosis and cancer. The pathogenesis of NAFLD involves a complex interaction among environmental factors (i.e., Western diet), obesity, changes in microbiota, and predisposing genetic variants resulting in a disturbed lipid homeostasis and an excessive accumulation of triglycerides and other lipid species in hepatocytes. Insulin resistance is a central mechanism that leads to lipotoxicity, endoplasmic reticulum stress, disturbed autophagy, and, ultimately, hepatocyte injury and death that triggers hepatic inflammation, hepatic stellate cell activation, and progressive fibrogenesis, thus driving disease progression. In the present review, we summarize the currently available data on the pathogenesis of NAFLD, emphasizing the most recent advances. A better understanding of NAFLD/NASH pathogenesis is crucial for the design of new and efficient therapeutic interventions.

Inflammation and hepatocyte injury and death are the hallmarks of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) through binding of surface-expressed pattern recognition receptors (PRRs), which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.

No abstract