Adaptive immunity: an emerging player in the progression of NAFLD

Sutti, Salvatore; Albano, Emanuele

doi:10.1038/s41575-019-0210-2

Cited by 263 publications

(281 citation statements)

References 133 publications

(263 reference statements)

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“…(70) Although innate immune mechanisms are considered a major contributing factor to the inflammatory process in NASH, recent evidence indicates that adaptive immunity has an important role in the progression of this disease. (71) Here, we highlight the major immune cell types involved in the progression of NASH.…”

Section: Mechanisms Of Inflammation Inflammation and Immune Dysregulamentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous group of liver diseases characterized by the accumulation of fat in the liver. The heterogeneity of NAFLD is reflected in a clinical and histologic spectrum where some patients develop isolated steatosis of the liver, termed nonalcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation, and consequent fibrosis, termed nonalcoholic steatohepatitis (NASH). Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid‐induced sublethal and lethal stress culminates in the activation of inflammatory processes, such as the release of proinflammatory extracellular vesicles and cell death. Innate and adaptive immune mechanisms involving macrophages, dendritic cells, and lymphocytes are central drivers of inflammation that recognize damage‐ and pathogen‐associated molecular patterns and contribute to the progression of the inflammatory cascade. While the activation of the innate immune system and the recruitment of proinflammatory monocytes into the liver in NASH are well known, the exact signals that lead to this remain less well defined. Further, the contribution of other immune cell types, such as neutrophils and B cells, is an area of intense research. Many host factors, such as the microbiome and gut–liver axis, modify individual susceptibility to NASH. In this review, we discuss lipotoxicity, inflammation, and the contribution of interorgan crosstalk in NASH pathogenesis.

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Section: Mechanisms Of Inflammation Inflammation and Immune Dysregulamentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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“…NAFLD is emerging as a worldwide public health threat (31). A number of patients with NAFLD develop a more inflammatory and progressive subtype-NASH, which can lead to cirrhosis and end-edge liver disease (32,33). The cornerstones of NAFLD treatment are weight loss and increased amounts of exercise, but maintaining these lifestyle changes can be hard.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

Huang

Fan

et al. 2020

Preprint

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Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that causes worldwide morbidity and mortality, yet there is still a lack of pharmacological therapies. Liver inflammation is an important contributor for disease progression from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH).We identified HDAC inhibitor givinostat as a potent inhibitor of macrophages inflammatory activation, and aimed to evaluate the therapeutic potential of givinostat for treatment of NASH. Daily administration of givoinostat (10mg/kg) alleviated inflammation and attenuated hepatic fibrosis in methionine-and choline-deficient diet (MCD)-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In hepatocyte givinostat reduced palmitic acid induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in fructose, palmitate, cholesterol diet (FPC) induced NASH mice. Givinostat attenuated hepatic steatosis, inflammation as well as liver injury in FPC-induced NASH. In conclusion, givinostat appears to be efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for treatment of human NASH.

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“…65,66 The lack of adaptive immunity in HLCM may also pose questions about its reliability for the study of metabolic liver disease and drug-induced liver injury (DILI) in certain aspects. [67][68][69][70] Fortunately, recent seminal studies have shown a framework that would alleviate this fundamental constraint by reconstituting the hu-manized adaptive immune system. 12,[71][72][73][74][75][76] This approach requires the transplantation of hematopoietic stem cells, preferably with the concurrent transplantation of bone marrow, spleen, and thymus from the same donor to reestablish the human adaptive immune system in HLCM.…”

Section: Current Limitations and Progress In Overcoming Themmentioning

confidence: 99%

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

et al. 2020

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Advancement in both bioengineering and cell biology of the liver led to the establishment of the first-generation humanized liver chimeric mouse (HLCM) model in 2001. The HLCM system was initially developed to satisfy the necessity for a convenient and physiologically representative small animal model for studies of hepatitis B virus and hepatitis C virus infection. Over the last two decades, the HLCM system has substantially evolved in quality, production capacity, and utility, thereby growing its versatility beyond the study of viral hepatitis. Hence, it has been increasingly employed for a variety of applications including, but not limited to, the investigation of drug metabolism and pharmacokinetics and stem cell biology. To date, more than a dozen distinctive HLCM systems have been established, and each model system has similarities as well as unique characteristics, which are often perplexing for end-users. Thus, this review aims to summarize the history, evolution, advantages, and pitfalls of each model system with the goal of providing comprehensive information that is necessary for researchers to implement the ideal HLCM system for their purposes. Furthermore, this review article summarizes the contribution of HLCM and its derivatives to our mechanistic understanding of various human liver diseases, its potential for novel applications, and its current limitations.

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Adaptive immunity: an emerging player in the progression of NAFLD

Cited by 263 publications

References 133 publications

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

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