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

• 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
• DOI: 10.1016/j.lfs.2013.09.013
• EISSN: 1879-0631
• ISSN: 0024-3205

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.