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Nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, L-amino acid-defined diet and the role of signal changes

Nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and even hepatocellular carcinoma (HCC). The incidence of NASH-associated HCC is increasing, posing a serious public health threat. Unfortunately, the underlying pathological mechanisms, including the possible differences between neoplast...

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Autores principales: Suzuki-Kemuriyama, Noriko, Abe, Akari, Nakane, Sae, Yuki, Megumi, Miyajima, Katsuhiro, Nakae, Dai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10399772/
https://www.ncbi.nlm.nih.gov/pubmed/37535625
http://dx.doi.org/10.1371/journal.pone.0287657
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author Suzuki-Kemuriyama, Noriko
Abe, Akari
Nakane, Sae
Yuki, Megumi
Miyajima, Katsuhiro
Nakae, Dai
author_facet Suzuki-Kemuriyama, Noriko
Abe, Akari
Nakane, Sae
Yuki, Megumi
Miyajima, Katsuhiro
Nakae, Dai
author_sort Suzuki-Kemuriyama, Noriko
collection PubMed
description Nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and even hepatocellular carcinoma (HCC). The incidence of NASH-associated HCC is increasing, posing a serious public health threat. Unfortunately, the underlying pathological mechanisms, including the possible differences between neoplastic and non-neoplastic lesions, remain largely unknown. Previously, we reported a dietary mouse NASH model with a choline-deficient, methionine-lowered, L-amino-acid-defined, high-fat diet containing shortening without trans fatty acids (CDAA-HF-T[−]), which rapidly induces fibrosis and proliferative lesions in the liver. This study aimed to develop a mouse CDAA-HF-T(−) model capable of assessing NASH-associated hepatocarcinogenesis and identifying key signaling factors involved in its underlying mechanisms. Multiple large masses, histopathologically hepatocellular adenomas and carcinomas, and hemangiosarcomas were detected in the liver samples of mice fed CDAA-HF-T(−) for 52 or 63 weeks, along with highly advanced fibrosis and numerous foamy, phagocytic macrophages in the adjacent nontumoral area. Multiple metastatic nodules were found in the lungs of one of the animals, and lymphoid clusters were found in all CDAA-HF-T(−) group mice. In the Ingenuity Pathways Analysis of RNA expression data, the CDAA-HF-T(−) feeding revealed common signal changes in nontumoral and tumoral liver tissues, including increased IL-8 and RhoGTPases signaling and decreased lipid metabolism. Meanwhile, macrophage inflammatory protein 2 (MIP-2) expression levels were upregulated in nontumoral liver tissue from the end of Week 13 of CDAA-HF-T(−) feeding to the end of Week 63. On the other hand, MIP-2 was expressed on macrophages in non-tumor areas and hepatocytes in tumor areas. Therefore, the CDAA-HF-T(−) mouse model is useful for assessing NASH and NASH-associated hepatocarcinogenesis, and IL-8 signaling plays important roles in NASH-associated carcinogenesis and cirrhosis, but it may also play different roles in nontumoral liver tissue and tumorigenesis.
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spelling pubmed-103997722023-08-04 Nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, L-amino acid-defined diet and the role of signal changes Suzuki-Kemuriyama, Noriko Abe, Akari Nakane, Sae Yuki, Megumi Miyajima, Katsuhiro Nakae, Dai PLoS One Research Article Nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and even hepatocellular carcinoma (HCC). The incidence of NASH-associated HCC is increasing, posing a serious public health threat. Unfortunately, the underlying pathological mechanisms, including the possible differences between neoplastic and non-neoplastic lesions, remain largely unknown. Previously, we reported a dietary mouse NASH model with a choline-deficient, methionine-lowered, L-amino-acid-defined, high-fat diet containing shortening without trans fatty acids (CDAA-HF-T[−]), which rapidly induces fibrosis and proliferative lesions in the liver. This study aimed to develop a mouse CDAA-HF-T(−) model capable of assessing NASH-associated hepatocarcinogenesis and identifying key signaling factors involved in its underlying mechanisms. Multiple large masses, histopathologically hepatocellular adenomas and carcinomas, and hemangiosarcomas were detected in the liver samples of mice fed CDAA-HF-T(−) for 52 or 63 weeks, along with highly advanced fibrosis and numerous foamy, phagocytic macrophages in the adjacent nontumoral area. Multiple metastatic nodules were found in the lungs of one of the animals, and lymphoid clusters were found in all CDAA-HF-T(−) group mice. In the Ingenuity Pathways Analysis of RNA expression data, the CDAA-HF-T(−) feeding revealed common signal changes in nontumoral and tumoral liver tissues, including increased IL-8 and RhoGTPases signaling and decreased lipid metabolism. Meanwhile, macrophage inflammatory protein 2 (MIP-2) expression levels were upregulated in nontumoral liver tissue from the end of Week 13 of CDAA-HF-T(−) feeding to the end of Week 63. On the other hand, MIP-2 was expressed on macrophages in non-tumor areas and hepatocytes in tumor areas. Therefore, the CDAA-HF-T(−) mouse model is useful for assessing NASH and NASH-associated hepatocarcinogenesis, and IL-8 signaling plays important roles in NASH-associated carcinogenesis and cirrhosis, but it may also play different roles in nontumoral liver tissue and tumorigenesis. Public Library of Science 2023-08-03 /pmc/articles/PMC10399772/ /pubmed/37535625 http://dx.doi.org/10.1371/journal.pone.0287657 Text en © 2023 Suzuki-Kemuriyama et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Suzuki-Kemuriyama, Noriko
Abe, Akari
Nakane, Sae
Yuki, Megumi
Miyajima, Katsuhiro
Nakae, Dai
Nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, L-amino acid-defined diet and the role of signal changes
title Nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, L-amino acid-defined diet and the role of signal changes
title_full Nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, L-amino acid-defined diet and the role of signal changes
title_fullStr Nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, L-amino acid-defined diet and the role of signal changes
title_full_unstemmed Nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, L-amino acid-defined diet and the role of signal changes
title_short Nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, L-amino acid-defined diet and the role of signal changes
title_sort nonalcoholic steatohepatitis-associated hepatocarcinogenesis in mice fed a modified choline-deficient, methionine-lowered, l-amino acid-defined diet and the role of signal changes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10399772/
https://www.ncbi.nlm.nih.gov/pubmed/37535625
http://dx.doi.org/10.1371/journal.pone.0287657
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