Severe steatosis and mild colitis are important for the early occurrence of hepatocellular carcinoma

Toshihiko, Sato; Tsuchiya, Atsunori; Owaki, Takashi; Kumagai, Motoki; Motegi, Satoko; Iwasawa, Takahiro; Nojiri, Shunsuke; Ogawa, Masahiro; Takeuchi, Suguru; Watanabe, Yusuke; Kawata, Yuzo; Kamimura, Hiroteru; Terai, Shuji

doi:10.1016/j.bbrc.2021.05.097

Cited by 6 publications

(7 citation statements)

References 22 publications

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“…Melanocortin 4 receptor-deficient ( Mc4r -KO) mice are ideal models for evaluating the effects of cell therapy and drugs against NASH [ 5 – 7 ]. MC4R is expressed in the hypothalamic nuclei and regulates food intake and body weight; thus, Mc4r -KO mice cannot control their appetite and exhibit symptoms such as obesity, insulin resistance, and liver steatosis similar to those of NASH in humans.…”

Section: Introductionmentioning

confidence: 99%

“…When a high-fat diet (HFD) was started 8 weeks after birth, steatohepatitis with fibrosis and hepatocellular carcinoma were detected around 28 weeks and 1 year after birth, respectively, in the mice [ 8 , 9 ]. Using this model, we had previously evaluated the anti-inflammatory and anti-fibrosis effects of mesenchymal stem cells and their exosomes, and the mechanisms of NASH-related carcinogenesis [ 5 – 7 ]. Thus, this mouse model is ideal for evaluating the effects of drugs against steatosis, fibrosis, and carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

et al. 2022

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Background ONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can also induce endogenous prostaglandin (PG)I2 and PGE2 levels. Furthermore, ONO-1301 acts as a cytokine inducer and can initiate tissue repair in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, cardiac infarction, and obstructive nephropathy. In this study, our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH). Methods The therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro. Results ONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells. Conclusions The results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

et al. 2022

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“…In addition, these mice display obesity and insulin resistance similar to humans; therefore, this model is ideal 4,5 . Using this model, we evaluated the effects of mesenchymal stem cells (MSCs) and their exosomes on NASH, 6 the role of sphingosine‐1‐phosphate and their receptors, 7 the relationship between intestinal inflammation and the development of HCC, 8 and the therapeutic effects of ONO‐1301 9 …”

Section: Introductionmentioning

confidence: 99%

Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non‐alcoholic steatohepatitis mouse model

Ishii

Tsuchiya

Natsui

et al. 2022

Hepatology Research

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Aim: Non-alcoholic steatohepatitis (NASH) with fibrosis eventually leads to cirrhosis and hepatocellular carcinoma. Thus, the development of therapies other than dietary restriction and exercise, particularly those that suppress steatosis and fibrosis of the liver and have a long-term beneficial effect, is necessary. We aimed to evaluate the therapeutic effects of the HMGB1 peptide synthesized from box A using the melanocortin-4 receptor-deficient (Mc4r-KO) NASH model mouse. Methods:We performed short-and long-term administration of this peptide and evaluated the effects on steatosis, fibrosis, and carcinogenesis using Mc4r-KO mice.We also analyzed the direct effect of this peptide on macrophages and hepatic stellate cells in vitro and performed lipidomics and metabolomics techniques to evaluate the effect.Results: Although this peptide did not show direct effects on macrophages and hepatic stellate cells in vitro, in the short-term administration model, we could confirm the reduction of liver damage, steatosis, and fibrosis progression. The results of lipidomics and metabolomics suggested that the peptide might ameliorate NASH by promoting lipolysis via the activation of fatty acid β-oxidation and improving insulin resistance. In the long-term administration model, this peptide prevented progression to cirrhosis but retained the steatosis state, that is, the peptide prevents the progression to "burnt-out NASH." This peptide inhibited carcinogenesis by about one-third. Conclusion:This HMGB1 peptide can reduce liver damage, improve fibrosis and steatosis, and inhibit carcinogenesis, suggesting that the peptide would be a new treatment candidate for NASH and can contribute to the long-term prognosis for patients with NASH.

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“…Liver injury can accelerate fatty acid flux to the liver, leading to increased levels of the hepatic content of total cholesterol (TC) and triglycerides (TG) ( Wang et al, 2019 ), which eventually causes NASH. In addition, it has been evident that DSS colitis promotes tumorigenesis in a HFD-induced NASH mice model ( Sato et al, 2021 ). In this context, combined administration of HFD and DSS induced NASH has been developed.…”

Section: Introductionmentioning

confidence: 99%

High-fat diet combined with dextran sulfate sodium failed to induce a more serious NASH phenotype than high-fat diet alone

et al. 2022

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Background and Aims: Animal models are essential tools to investigate the pathogenesis of diseases. Disruption in the intestinal epithelial barrier and gut vascular barrier is an early event in the development of non-alcoholic fatty liver disease (NAFLD). Intestinal epithelial barrier can be destroyed by dextran sulfate sodium (DSS) oral administration. High fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH) rat model has been widely used. Recently, the combination of HFD with DSS induced NASH model has also been reported. The present study aimed to evaluate whether this composite NASH animal model is more ideal than that induced by HFD alone.Methods: Rats were divided into control, HFD and HFD combined with DSS (DSS + HFD) groups. They were fed with routine diet, high-fat diet, and HFD combined with DSS drinking, respectively, for 22 weeks. Histopathological analysis (HE staining, Oil-Red O staining, Masson staining), lipid parameters testing (TG, TC, GLU, NEFA, TRIG, LDL, HDL), testing on indicators of inflammation (TNF-α, ALT, AST, ALP, LDH) and oxidative stress (MDA, SOD, CAT) were performed.Results: Rats in HFD and DSS + HFD group displayed increase in the body weight, liver weight, lipids accumulation and the levels of TNF-α, ALT, AST, ALP, MDA in serum and liver accompanied with impaired glucose tolerance, obvious hepatitis, and decreased levels of SOD and CAT in serum and liver compared to those in control group. Moreover, in the DSS + HFD group, but not in the HFD group, proliferation of fibrous tissue in the portal area and the hepatic lobules was found.Conclusion: The addition of DSS on high-fat diet did not exacerbate lipid accumulation and inflammation, but induced NASH-related liver fibrosis.

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Severe steatosis and mild colitis are important for the early occurrence of hepatocellular carcinoma

Cited by 6 publications

References 22 publications

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

A novel prostaglandin I2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice

Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non‐alcoholic steatohepatitis mouse model

High-fat diet combined with dextran sulfate sodium failed to induce a more serious NASH phenotype than high-fat diet alone

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