Mechanisms of NAFLD development and therapeutic strategies

Friedman, Scott L.; Neuschwander‐Tetri, Brent A.; Rinella, Mary E.; Sanyal, Arun J.

doi:10.1038/s41591-018-0104-9

Cited by 2,620 publications

(2,504 citation statements)

References 179 publications

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“…). Insulin resistance (IR) and NAFLD are crucially linked; IR leads to reduced glucose uptake in adipocytes and muscles, and hepatocytes can secrete dipeptidyl peptidase 4, which promotes adipose tissue inflammation and IR …”

Section: Steatosis and Lipotoxicitymentioning

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: Steatosis and Lipotoxicitymentioning

confidence: 99%

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

2020

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“…Hepatic fibrosis occurs not only in patients with chronic liver disease, including non‐alcoholic fatty liver disease (NAFLD), but also in patients with other lifestyle‐related diseases, including obesity, diabetes mellitus, hypertension, and chronic kidney injury . As hepatic fibrosis progresses, patients are at a higher risk of developing life‐threatening complications, including hepatocellular carcinoma and cardiovascular diseases . Thus, it is important to estimate the staging of hepatic fibrosis in the management of patients with various internal diseases.…”

Section: Introductionmentioning

confidence: 99%

Profiles of advanced hepatic fibrosis evaluated by FIB‐4 index and shear wave elastography in health checkup examinees

Yamamura

Kawaguchi

Nakano

et al. 2019

Hepatology Research

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Aim Advanced hepatic fibrosis is seen in individuals with potential hepatocellular carcinoma and cardiovascular disease. Hepatic fibrosis can be assessed using a combination of the FIB‐4 index and imaging modalities, including shear wave elastography. We aimed to investigate the prevalence of advanced fibrosis in the general population and the profiles associated with advanced fibrosis using a data‐mining analysis. Methods We enrolled 1155 health checkup examinees (median age 53 years, 685 women, 470 male). Advanced fibrosis was defined by FIB‐4 index ≥1.3 and liver stiffness ≥8.07 kPa using shear wave elastography. Participants were classified as normal‐mild fibrosis (n = 1035) or advanced fibrosis (n = 120). Factors associated with advanced fibrosis were analyzed by logistic regression and decision‐tree analyses. Results Advanced fibrosis was observed in 10.4% of participants (120/1155). In the logistic regression analysis, independent factors for advanced fibrosis were age (≥75 years; OR 2.12, 95% CI 1.021–4.415; P = 0.0419) and the presence of metabolic syndrome (OR 2.51, 95% CI 1.416–4.462; P = 0.0017). The decision‐tree analysis showed two profiles associated with advanced fibrosis: profile 1 – individuals aged ≥65 years with metabolic syndrome and mild‐to‐moderate alcohol consumption (prevalence of advanced fibrosis 73.3%); and profile 2 – individuals without metabolic syndrome, aged ≥75 years, with no exercise habit (prevalence of advanced fibrosis 56.3%). Conclusions Advanced fibrosis was observed in 10.4% of health checkup examinees. Furthermore, we showed that aging, metabolic syndrome with mild‐to‐moderate alcohol consumption, and physical inactivity were associated with advanced fibrosis. Thus, prevention of metabolic syndrome and alcohol withdrawal, as well as exercise habits, might inhibit the progression of hepatic fibrosis.

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“…Characterized by hepatocyte damage, severe inflammation, and fibrosis, NASH is a complex process that results from multiple injury and repair responses triggered by lipotoxicity . Hepatocytes are the chief lipid‐handling cells and function as one of the earliest responders in response to lipotoxicity .…”

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confidence: 99%

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

Wang

Wen

et al. 2019

Hepatology

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Activation of apoptosis signal‐regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte‐derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor–associated factor 6 (TRAF6) promotes lysine 6 (Lys6)‐linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the in vitro findings, diet‐induced liver inflammation and fibrosis were substantially attenuated in Traf6+/– mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6‐linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N‐terminal dimerization of ASK1, resulting in the boosted activation of ASK1‐c‐Jun N‐terminal kinase 1/2 (JNK1/2)‐mitogen‐activated protein kinase 14(p38) signaling cascade in hepatocytes. Conclusion: These results suggest that Lys6‐linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6‐linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.

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Mechanisms of NAFLD development and therapeutic strategies

Cited by 2,620 publications

References 179 publications

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Pathogenesis of Nonalcoholic Steatohepatitis: An Overview

Profiles of advanced hepatic fibrosis evaluated by FIB‐4 index and shear wave elastography in health checkup examinees

Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1

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