High-fat-cholesterol diet mainly induced necrosis in fibrotic steatohepatitis rat by suppressing caspase activity

Husna Yetti, Hisao Naito, Xiaofang Jia, Moritaka Shindo, Hitoshi Taki, Hazuki Tamada, Kazuya Kitamori, Yumi Hayashi, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Aim Apoptosis and necrosis occur in nonalcoholic steatohepatitis (NASH) and are thought to be related to fibrosis. A stroke-prone spontaneously hypertensive (SHRSP5/Dmcr) rat fed a high-fat-cholesterol (HFC) diet exhibited similar pathological features to human NASH with severe liver fibrosis. We aimed to reveal the molecular pathway and to confirm the relationship between cell death, fibrosis and K18Asp396 levels, a neoepitope generated during cleavage of keratin 18 by caspases, as a candidate for biomarker of hepatic damage in this animal model. Main methods Male rats were fed with control and HFC diets for 2, 8 and 14 weeks. Liver apoptosis cells, necrosis score, and the molecular mechanism and K18Asp396 levels were investigated. Key findings HFC diet increased TUNEL-positive cells only at 2 weeks and necrosis scores strongly in the livers of rats during the entire period. This diet increased hepatic Bax/Bak but decreased Bcl-2/Bcl-xl expression during the entire period; however, it upregulated caspase 8, 9, and 3/7 activities only at 2 weeks, but downregulated them at 14 weeks. Additionally, this diet did not increase hepatic cytochrome c expression. Serum K18Asp396 levels have a positive correlation with necrosis score. Significance In SHRSP5/Dmcr rats, HFC diet caused hepatocyte necrosis rather than apoptosis by the downregulation of all caspase activity. Serum K18Asp396 levels may be a good biomarker of hepatocyte necrosis.

Original languageEnglish
Pages (from-to)673-680
Number of pages8
JournalLife Sciences
Issue number18-19
Publication statusPublished - 04-11-2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Pharmacology, Toxicology and Pharmaceutics
  • General Biochemistry,Genetics and Molecular Biology


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