A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer

Tsuchida, Takuma; Lee, Youngmin A.; Fujiwara, Naoto; Ybanez, Maria D.; Allen, Brittany; Martins, S R; Fiel, M. Isabel; Goossens, Nicolas; Chou, Hsin I.; Hoshida, Yujin; Friedman, Scott L.

doi:10.1016/j.jhep.2018.03.011

Cited by 361 publications

(336 citation statements)

References 53 publications

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“…Likewise, the administration of DEN to CD+HFD-fed mice allows for much more efficient HCC induction (Kishida et al, 2016), although it does not model NASH-induced HCC. Another recently developed model has combined Western diet (WD) with weekly dosing of carbon tetrachloride (CCl 4 ) (Tsuchida et al, 2018). This model has the advantage of rapid disease progression, as the mice develop stage 3 fibrosis by 12 weeks and HCC by 24 weeks.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

et al. 2019

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Hepatocellular carcinoma (HCC) is one of the most fatal and fastest growing cancers. Recently, nonalcoholic steatohepatitis (NASH) has been recognized as a major HCC catalyst. However, it is difficult to decipher the molecular mechanisms underlying the pathogenesis of NASH and understand how it progresses to HCC by studying humans. Progress in this field depends on the availability of reliable preclinical models amenable to genetic and functional analyses and exhibit robust NASH to HCC progression. Although numerous mouse models of NASH have been described, many do not faithfully mimic the human disease and few reliably progress to HCC. Here, we review current literature on the molecular etiology of NASH-related HCC and critically evaluate existing mouse models and their suitability for studying this malignancy. We also compare human transcriptomic and histopathological profiles with data from MUP-uPA mice, a reliable model of NASH-driven HCC that has been useful for evaluation of HCC-targeting immunotherapies.

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Section: Introductionmentioning

confidence: 99%

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

et al. 2019

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“…Hepatic lipid overloading is also proposed to disrupt of the redox balance, contributing to accumulation of reactive oxygen species (ROS), then abrogating antioxidant response . In CDHFD and TAA‐induced NASH rat model, lipid accumulation and TAA metabolism are responsible for fatty acid oxidization, generating lipid hydroperoxides . A. lappa root interventions decreased the levels of these byproducts in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…In In human and murine diet-NAFLD models, the increase in total fatty acid levels is positively correlated to liver lipogenesis and play critical roles in the establishment and progression of this disease. 7,8,34 in vitro data from HCC cell lines (HepG2 and Huh7) suggest that palmitic acid increases fatty acid uptake via upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) and cluster of differentiation 36 (CD36) protein expression, subsequently leading to oxidative and endoplasmic reticulum stress. 35 Moreover, the increase in the levels of arachidonic and linoleic acid metabolites has been proposed as a biomarker for different stages of NAFLD.…”

Section: A Lappa Root Decreases Oxidative Stress In the Livermentioning

confidence: 99%

“…When HFD is combined to methionine‐choline deficiency, fat β‐oxidation, and very low‐density lipoprotein production and secretion are impaired, aggravating steatosis and inflammation (the “second hit”) . Dietary interventions may also be associated to repetitive chemical insult, as thioacetamide (TAA) and carbon tetrachloride (CCl 4 ) administrations . After TAA liver metabolism, highly reactive sulfoxide (TASO) and sulfdioxide (TASO 2 ) metabolites are generated, promoting necroinflammatory (the “second hit”) and fibrotic/cirrhotic responses .…”

Section: Introductionmentioning

confidence: 99%

“…6 Dietary interventions may also be associated to repetitive chemical insult, as thioacetamide (TAA) and carbon tetrachloride (CCl 4 ) administrations. 7,8 After TAA liver metabolism, highly reactive sulfoxide (TASO) and sulfdioxide (TASO 2 ) metabolites are generated, promoting necroinflammatory (the "second hit") and fibrotic/ cirrhotic responses. 8,9 In addition to steatohepatitis, TAA-mediated oxidative damage may contribute to genomic instability and to the development of preneoplastic foci positive for glutathione-S-transferase pi (GST-P), considered preneoplastic lesions (PNLs) and biomarkers of early hepatocarcinogenesis.…”

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confidence: 99%

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Burdock (Arctium lappa L.) root attenuates preneoplastic lesion development in a diet and thioacetamide‐induced model of steatohepatitis‐associated hepatocarcinogenesis

Romualdo

Silva

et al. 2019

Environmental Toxicology

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Nonalcoholic steatohepatitis (NASH) is considered growing risk factor for hepatocellular carcinoma development in high‐income countries. Diet‐ and chemically induced rodent models have been applied for the translational study of NASH‐associated hepatocarcinogenesis due to their morphological and molecular similarities to the corresponding human disease. Arctium lappa L. (burdock) root tea has been extensively consumed in Traditional Chinese Medicine due to its potential therapeutic properties. Indeed, the bioactive compounds of A. lappa root, as the polyphenols, have already showed antioxidant and anti‐inflammatory properties in different in vivo and in vitro bioassays. In this study, we investigated whether burdock root ethanolic extract (BRE) administration attenuates NASH‐associated hepatocarcinogenesis. Eight‐week‐old male Wistar rats received choline‐deficient high‐fat diet for 8 weeks and multiple thioacetamide doses for 4 weeks in order to induce NASH and preneoplastic glutathione‐S‐transferase pi (GST‐P)+ preneoplastic foci. Subsequently, rats were treated with BRE (100 or 200 mg/kg body weight) or vehicle by oral gavage for 2 weeks. BRE displayed high levels of chlorogenic and caffeic acids and BRE administration reduced total fatty acid and lipid hydroperoxide levels, while increasing the activities of antioxidant superoxide dismutase and catalase enzymes in the liver. Furthermore, burdock intervention diminished the size of GST‐P+ remodeling preneoplastic lesions (PNLs) and displayed a trend on reducing hepatocyte proliferation (Ki‐67) inside them. These findings suggest that short‐term exposure to BRE alleviated remodeling PNL development in NASH‐associated hepatocarcinogenesis.

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TACE inhibition: a promising therapeutic intervention against AATF‐mediated steatohepatitis to hepatocarcinogenesis

Srinivas,

Suresh,

Vishwanath

et al. 2024

Molecular Oncology

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Metabolic dysfunction‐associated steatohepatitis‐driven hepatocellular carcinoma (MASH‐HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor‐alpha (TNF‐α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF‐α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF‐mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH‐HCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2 μL·g−1, weekly) for 24 weeks. TACE activity, TNF‐α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12 weeks and advanced fibrosis with HCC at 24 weeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNF‐α, which upregulated AATF, a key molecular driver of MASH‐HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATF‐mediated inflammation, fibrosis, and oncogenesis in MASH‐HCC, offering a potential target for therapeutic intervention.

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A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer

Cited by 361 publications

References 53 publications

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

Burdock (Arctium lappa L.) root attenuates preneoplastic lesion development in a diet and thioacetamide‐induced model of steatohepatitis‐associated hepatocarcinogenesis

TACE inhibition: a promising therapeutic intervention against AATF‐mediated steatohepatitis to hepatocarcinogenesis

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