title: Increased hepatic apoptosis in high-fat diet-induced NASH in rats may be associated with downregulation of hepatic stimulator substance.
abstract: The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Hepatocellular apoptosis could be one of the key factors in the pathogenesis of non-alcoholic steatohepatitis (NASH). Hepatic stimulator substance (HSS) protects liver cells from various toxins. We previously reported that HSS is critically important for the survival of hepatocytes due to its mitochondrial association. This study aims to investigate the relationship between HSS and hepatocellular apoptosis in vivo models of high-fat diet-induced NASH and in vitro models of palmitic acid-induced hepatocyte injury. Sprague-Dawley rats were fed a high-fat diet for 8, 12 and 16 weeks. Hepatic histological lesions, liver function and apoptosis were examined. HSS expression, in association with caspase-3 and cytochrome c leakage, which are both indicators of cell apoptosis, was measured. Results showed that a high-fat diet altered liver function and histology in a manner resembling NASH. Hepatic protein and mRNA HSS expression was decreased as NASH progressed. Meanwhile, cell apoptosis increased as result of caspase-3 activation and cytochrome c release, indicating that HSS might be involved in NASH pathogenesis. Furthermore, in palmitic acid-induced hepatic cell damage, over-expression of HSS decreased cells apoptosis. In contrast, repression of HSS expression by siRNA increased cell apoptosis. In conclusion, these data imply that cell apoptosis contributes to the pathogenesis of NASH, during which HSS expression is downregulated. Increasing HSS expression in hepatocytes may forestall cell apoptosis as result of fatty acid insult.
authors.affiliation: Department of Cell Biology and Municipal Laboratory for Liver Protection and Regulation of Liver Regeneration, Capital Medical University, Beijing, China. jiangy@ccmu.edu.cn
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Miaoyun
authors.initials: M
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: An
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015536:Down-Regulation; D005234:Fatty Liver / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C073456:hepatic stimulator substance; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D053148:Caspase 3