title: A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein.
abstract: Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome that is characterized by steatosis, inflammation, and fibrosis, and may progress to cirrhosis and carcinoma. To investigate its pathogenic processes, we established a novel murine model for NASH by combination of a high-fat diet (HFD) and oxidized low-density lipoprotein (oxLDL). Mice that received HFD for 23 weeks showed hepatic steatosis, slight fibrosis, and a high level of lipid peroxidation compared with a regular diet (RD)-fed mice. Hepatic injury and elevated tumor necrosis factor (TNF)-α mRNA expression were also detected in these mice. Moreover, oxLDL administration to HFD-fed mice during weeks 21-23 not only aggravated hepatic steatosis, fibrosis, and lipid metabolism, but also resulted in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH. Inflammation was accompanied by increased gene expression of TNF-α and interleukin (IL)-6. Additionally, the livers of RD-fed animals treated with oxLDL during weeks 21-23 were characterized by foamy macrophages and inflammatory cell infiltration along with an elevated IL-6 mRNA level. These results suggest that an increased oxidative state, including HFD-induced intracellular lipid peroxidation and its extracellular source from oxLDL, is the actual trigger for hepatic inflammation in which liver injury is mediated by TNF-α and inflammatory cell accumulation is dependent on IL-6. HFD and oxLDL also induced insulin resistance in mice; additionally, oxLDL downregulated insulin secretion. In this model, CD36 overexpression was observed in the hepatocytes of HFD-fed mice and those treated with HFD and oxLDL, and in the hepatic macrophages of RD-fed mice immediately after oxLDL treatment. In vitro experiments indicated a rapid and transient elevation of CD36 on macrophage plasma membrane in response to oxLDL. Our findings demonstrate that CD36 expressed on hepatocytes and hepatic macrophages mediates the pathophysiology of NASH.
authors: Department of Advanced Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
authors: Yimin
authors: Hiroaki
authors: H
authors: Furumaki
authors: Shiho
authors: S
authors: Matsuoka
authors: Toshihiro
authors: T
authors: Sakurai
authors: Masashi
authors: M
authors: Kohanawa
authors: Songji
authors: S
authors: Zhao
authors: Yuji
authors: Y
authors: Kuge
authors: Nagara
authors: N
authors: Tamaki
authors: Hitoshi
authors: H
authors: Chiba
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000150:complications / Q000209:etiology* / Q000503:physiopathology; D015850:Interleukin-6 / Q000235:genetics; D008077:Lipoproteins, LDL / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D017931:DNA Primers; D004041:Dietary Fats; D015850:Interleukin-6; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein