Disease pathways and molecular mechanisms of nonalcoholic steatohepatitis

Wegermann, Kara; Diehl, Anna Mae; Moylan, Cynthia A.

doi:10.1002/cld.709

Cited by 13 publications

(9 citation statements)

References 18 publications

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“…In contrast, a multinational prospective study of 458 NAFLD patients by Vilar-Gomez et al reported that steatosis is significantly associated with a higher risk of death and liver-related complications, which aligns with the findings of this review, showcasing that NASH is associated with a significant burden and poor long-term prognosis [76]. It is important to note that because the exact cause of NAFLD and NASH is not yet understood, it is difficult to accurately assess the underlying factors for progression [5–7]. Therefore, further research into the cause of this disease is recommended to improve our understanding of disease progression and the key factors at play.…”

Section: Discussionsupporting

confidence: 80%

“…The exact cause of NAFLD to NASH progression is unknown and is likely due to a complex interplay of environmental and genetic factors; however, certain health conditions, such as obesity, high blood pressure and diabetes, increase the risk of it developing [3, 4]. Numerous genetic, epigenetic and environmental contributors have recently been proposed as the cause of NAFLD and NASH, including smoking and altered copper bioavailability [5–7].…”

Section: Introductionmentioning

confidence: 99%

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A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH)

et al. 2019

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IntroductionNon-Alcoholic Steatohepatitis (NASH) is a chronic, progressive disease characterized by fatty liver and liver cell injury, advancing to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Diagnosis involves liver biopsy; however, as a result of its high cost and invasiveness, NASH remains underdiagnosed, and accurate burden of disease (BoD) data are lacking. Our aim was to understand the epidemiological and BoD landscape in NASH and identify knowledge gaps.MethodsThe Ovid search engine was used to conduct a structured review, following quality systematic principles. It included publications that reported on epidemiology, quality of life (QoL) and BoD outcomes in NASH adults. Searches were limited to English language studies published between January 2007 and September 2017. Additional grey literature searches were conducted. A total of 53 references were selected; 38 were peer-reviewed and 15 were grey literature sources.ResultsNASH is estimated to affect 3–5% of the global population, most suffering from several comorbidities. Advancing fibrosis drives clinical outcomes, with approximately 20% of patients developing cirrhosis and/or HCC, the latter being a leading cause of death in NASH. A recent model predicted the 15-year survival of advanced fibrosis patients at F3 and F4 as 51.0% and 28.4%, respectively. The limited data consistently show that NASH patients experience significantly poorer QoL and higher costs compared to non-NASH patients.ConclusionThis first broad-ranging examination of NASH literature revealed a paucity of evidence, with poor-quality, small studies found. The overwhelming impact of NASH and its patient and healthcare burden is evident. Further evidence is needed to improve our understanding of NASH, especially as fibrosis stages advance.FundingGilead Science Inc.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-00960-3) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH)

et al. 2019

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“…Nowadays, finding a reliable animal model of NASH to better understand the pathophysiology of the disease, to identify novel biomarkers and to find new targets for therapy, is still a scientific challenge. An ideal NASH animal model should mimic the full spectrum of the human disease [4]. In this regard, in the present study, we develop and characterize a new male-rat model of NASH that exhibits the major clinical characteristics of the human pathology: metabolic syndrome, hepatic steatosis, lipotoxicity, hepatic cell death, hepatic inflammation, hepatic fibrosis, and portal hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…In view of the increasing incidence of NAFLD worldwide, a large number of translational laboratories are focused on understanding new aspects of NASH pathophysiology, on discovering specific and non-invasive diagnostic biomarkers, and developing effective pharmacologic treatments [4]. Nevertheless, the lack of reliable NASH animal models remains a limitation for studying the disease and for developing new therapeutic strategies [5].…”

Section: Introductionmentioning

confidence: 99%

New Rat Model of Advanced NASH Mimicking Pathophysiological Features and Transcriptomic Signature of The Human Disease

Maeso‐Díaz

Boyer‐Díaz²,

Lozano

et al. 2019

Cells

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Non-alcoholic steatohepatitis (NASH) is a major cause of chronic liver disease. However, most available animal models fail to reflect the whole spectrum of the disease. Liver fibrosis and portal hypertension are the strongest prognostic markers in advanced NASH. We herein aimed at developing a new model of NASH in male rats, obtained using a multi-hit protocol that combines the administration of a high fat and high-cholesterol diet with CCl4 and phenobarbital. Following this protocol, rats showed the full characteristics of advanced human NASH after 10 weeks and NASH with cirrhosis by 24 weeks. Specifically, our NASH rats exhibited: steatosis and metabolic syndrome, lipotoxicity, hepatocellular ballooning necrosis, inflammation and importantly, marked hepatic fibrosis and significant portal hypertension. Furthermore, a whole transcriptomic analysis of liver tissue from our rat model using next generation sequencing was compared with human NASH and illustrated the similarity of this pre-clinical model with the human disease. Pathway enrichment analysis showed that NASH animals shared a relevant number of central pathways involved in NASH pathophysiology, such as those related with cell death, as well as inflammatory or matrix remodeling. The present study defines a pre-clinical model of moderate and advanced NASH that mimics the human disease, including pathophysiologic characteristics and transcriptomic signature.

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“…Tremendous progress has been made in our understanding of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) (1)(2)(3), including the identification of several molecular pathways impacting a number of cell types (hepatocytes, macrophages, stellate cells) and organ systems, ranging from the liver to adipose tissue, the gut, immune system, and kidney (4,5). Yet, few if any of these pathways explicitly involve skeletal muscle, the principal organ responsible for glucose disposal (6) and energy homeostasis (7), key processes that can impact the core pathogenesis of a systemic metabolic disease such as NAFLD (8).…”

Section: Introductionmentioning

confidence: 99%

Harnessing Muscle–Liver Crosstalk to Treat Nonalcoholic Steatohepatitis

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions, affecting an estimated one-quarter of the world’s adult population. Multiple organ systems have been implicated in the pathophysiology of NAFLD; however, the role of skeletal muscle has until recently been largely overlooked. A growing body of evidence places skeletal muscle—via its impact on insulin resistance and systemic inflammation—and the muscle-liver axis at the center of the NAFLD pathogenic cascade. Population-based studies suggest that sarcopenia is an effect-modifier across the NAFLD spectrum in that it is tightly linked to an increased risk of non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis, all independent of obesity and insulin resistance. Longitudinal studies suggest that increases in skeletal muscle mass over time may both reduce the incidence of NAFLD and improve preexisting NAFLD. Adverse muscle composition, comprising both low muscle volume and high muscle fat infiltration (myosteatosis), is highly prevalent in patients with NAFLD. The risk of functional disability conferred by low muscle volume in NAFLD is further exacerbated by the presence of myosteatosis, which is twice as common in NAFLD as in other chronic liver diseases. Crosstalk between muscle and liver is influenced by several factors, including obesity, physical inactivity, ectopic fat deposition, oxidative stress, and proinflammatory mediators. In this perspective review, we discuss key pathophysiological processes driving sarcopenia in NAFLD: anabolic resistance, insulin resistance, metabolic inflexibility and systemic inflammation. Interventions that modify muscle quantity (mass), muscle quality (fat), and physical function by simultaneously engaging multiple targets and pathways implicated in muscle-liver crosstalk may be required to address the multifactorial pathogenesis of NAFLD/NASH and provide effective and durable therapies.

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Disease pathways and molecular mechanisms of nonalcoholic steatohepatitis

Abstract: http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/11-4-reading-wegermann a video presentation of this article

Cited by 13 publications

References 18 publications

A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH)

A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH)

New Rat Model of Advanced NASH Mimicking Pathophysiological Features and Transcriptomic Signature of The Human Disease

Harnessing Muscle–Liver Crosstalk to Treat Nonalcoholic Steatohepatitis

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