An update on animal models of liver fibrosis

Wu, ShuTing; Wang, Xinxin; Xing, WenBo; Li, FenYao; Liang, Ming; Li, KeShen; He, Ya‐Ling; Wang, Jianming

doi:10.3389/fmed.2023.1160053

Cited by 17 publications

(3 citation statements)

References 166 publications

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“…The changes induced by these conditions, such as altered liver vascular formation, modifications in the extracellular matrix composition, and impacts on drug metabolism, emphasize the necessity of employing animal models that effectively combine features of both cirrhosis and liver cancer. These models are instrumental in investigating the mechanisms through which anti-tumor drugs influence tumor initiation and development 4,11,12 .…”

Section: Discussionmentioning

confidence: 99%

A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide

Hu,

Kurihara,

Sun

et al. 2024

Preprint

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, and commonly associated with hepatic fibrosis or cirrhosis. This study aims to establish a rat model mimicking the progression from liver fibrosis to cirrhosis and subsequently to HCC using thioacetamide (TAA). We utilized male Lewis rats, treating them with intra-peritoneal injections of TAA. These rats received bi-weekly injections of either 200 mg/kg TAA or saline (as a control) over a period of 34 weeks. The development of cirrhosis and hepatocarcinogenesis was monitored through histopathological examinations, biochemical markers, and immunohistochemical analyses. Our results demonstrated that chronic TAA administration induced cirrhosis and well-differentiated HCC, characterized by increased fibrosis, altered liver architecture, and enhanced hepatocyte proliferation. Biochemical analyses revealed significant alterations in liver function markers, including elevated alpha-fetoprotein (AFP) levels, without affecting kidney function or causing significant weight loss or mortality in rats. This TAA-induced cirrhosis and HCC rat model successfully replicates the clinical progression of human HCC, including liver function impairment and early-stage liver cancer characteristics. It presents a valuable tool for future research on the mechanisms of antitumor drugs in tumor initiation and development.

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Section: Discussionmentioning

confidence: 99%

A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide

Hu,

Kurihara,

Sun

et al. 2024

Preprint

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“…To examine the function of DDB1 in the development of MASH, we challenged WT and LKO mice with MCD, which is the favored approach to research MASH pathogenesis. Although the MCD diet has some drawbacks, such as causing weight loss and lack of systemic insulin resistance, 34 it is more effective and repeatable in inducing severe liver injury and progressive fibrosis and is suitable for researching the mechanisms underlying MASH-related inflammation and fibrosis as well as strategies for preventing these conditions, compared to the HFD diet 35,36 …”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-specific loss of DDB1 attenuates hepatic steatosis but aggravates liver inflammation and fibrosis in MASH

Gu,

Chang,

Jin

et al. 2024

Hepatology Communications

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Background: MASH is a common clinical disease that can lead to advanced liver conditions, but no approved pharmacotherapies are available due to an incomplete understanding of its pathogenesis. Damaged DNA binding protein 1 (DDB1) participates in lipid metabolism. Nevertheless, the function of DDB1 in MASH is unclear. Methods: Clinical liver samples were obtained from patients with MASH and control individuals by liver biopsy. Hepatocyte-specific Ddb1-knockout mice and liver Hmgb1 knockdown mice were fed with a methionine-and choline-deficient diet to induce MASH. Results: We found that the expression of DDB1 in the liver was significantly decreased in MASH models. Hepatocyte-specific ablation of DDB1 markedly alleviated methionine-and choline-deficient diet-induced liver steatosis but unexpectedly exacerbated inflammation and fibrosis. Mechanistically, DDB1 deficiency attenuated hepatic steatosis by downregulating the expression of lipid synthesis and uptake genes. We identified high-mobility group box 1 as a key candidate target for DDB1-mediated liver injury. DDB1 deficiency upregulated the expression and extracellular release of high-mobility group box 1, which further increased macrophage infiltration and activated HSCs, ultimately leading to the exacerbation of liver inflammation and fibrosis. Conclusions: These data demonstrate the independent regulation of hepatic steatosis and injury in MASH. These findings have considerable clinical implications for the development of therapeutic strategies for MASH.

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“…In conclusion, this study establishes a protocol for TA-induced liver fibrosis in microminipigs. This 8-week protocol is considered an early establishment by several methods for animal fibrosis models 56 . Furthermore, the acute and chronic phases after injecting TA were partially elucidated in a large animal model for the first time.…”

Section: Discussionmentioning

confidence: 99%

A thioacetamide-induced liver fibrosis model for pre-clinical studies in microminipig

Nishi,

Yagi,

Ohtomo

et al. 2023

Sci Rep

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Drug-induced liver fibrosis models are used in normal and immunosuppressed small animals for transplantation and regenerative medicine to improve liver fibrosis. Although large animal models are needed for pre-clinical studies, they are yet to be established owing to drug sensitivity in animal species and difficulty in setting doses. In this study, we evaluated liver fibrosis by administering thioacetamide (TA) to normal microminipig and thymectomized microminipig; 3 times for 1 week (total duration: 8 weeks). The pigs treated with TA showed elevated blood cytokine levels and a continuous liver injury at 8 weeks. RNA-seq of the liver showed increased expression of fibrosis-related genes after TA treatment. Histopathological examination showed degenerative necrosis of hepatocytes around the central vein, and revealed fibrogenesis and hepatocyte proliferation. TA treatment caused CD3-positive T cells and macrophages scattered within the hepatic lobule to congregate near the center of the lobule and increased αSMA-positive cells. Thymectomized pigs showed liver fibrosis similar to that of normal pigs, although the clinical signs tended to be milder. This model is similar to pathogenesis of liver fibrosis reported in other animal models. Therefore, it is expected to contribute to research as a drug discovery and pre-clinical transplantation models.

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An update on animal models of liver fibrosis

Cited by 17 publications

References 166 publications

A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide

A rat model of cirrhosis with well-differentiated hepatocellular carcinoma induced by thioacetamide

Hepatocyte-specific loss of DDB1 attenuates hepatic steatosis but aggravates liver inflammation and fibrosis in MASH

A thioacetamide-induced liver fibrosis model for pre-clinical studies in microminipig

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