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

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...

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Bibliographic Details
Published in:	Life sciences (1973) Vol. 93; no. 18-19; pp. 673 - 680
Main Authors:	Yetti, Husna, Naito, Hisao, Jia, Xiaofang, Shindo, Moritaka, Taki, Hitoshi, Tamada, Hazuki, Kitamori, Kazuya, Hayashi, Yumi, Ikeda, Katsumi, Yamori, Yukio, Nakajima, Tamie
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Inc 04-11-2013
Subjects:	animal models Animals Apoptosis biomarkers blood serum Caspase activity Caspase Inhibitors - pharmacology caspases Caspases - metabolism Cholesterol, Dietary - administration & dosage Cholesterol, Dietary - adverse effects cytochrome c diet Diet, High-Fat - adverse effects Enzyme Activation - drug effects Enzyme Activation - physiology fatty liver Fatty Liver - enzymology Fatty Liver - pathology fibrosis Hepatic necrosis High-fat-cholesterol diet humans K18Asp396 keratin liver liver cirrhosis Liver Cirrhosis, Experimental - enzymology Liver Cirrhosis, Experimental - pathology Male Necrosis Non-alcoholic Fatty Liver Disease Rats Rats, Inbred SHR Hepatic necrosis K18Asp396 Caspase activity High-fat-cholesterol diet Apoptosis
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Summary:	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. Male rats were fed with control and HFC diets for 2, 8 and 14weeks. Liver apoptosis cells, necrosis score, and the molecular mechanism and K18Asp396 levels were investigated. HFC diet increased TUNEL-positive cells only at 2weeks 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 2weeks, but downregulated them at 14weeks. Additionally, this diet did not increase hepatic cytochrome c expression. Serum K18Asp396 levels have a positive correlation with necrosis score. 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.
Bibliography:	http://dx.doi.org/10.1016/j.lfs.2013.09.013 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0024-3205 1879-0631
DOI:	10.1016/j.lfs.2013.09.013