title: The roles of ER stress and P450 2E1 in CCl(4)-induced steatosis.
abstract: The role of ER stress on hepatic steatosis was investigated in a rat model. We injected CCl(4) into rats and found that CCl(4) could induce hepatic lipid accumulation, confirmed by Oil Red O staining and by measurement of triglyceride and cholesterol. The expression of ApoB, an apolipoprotein, was decreased in plasma and increased in the liver of CCl(4)-treated animals. The ER stress response was also significantly increased by CCl(4). P450 2E1 expression and activity were increased through interactions of P450 2E1 with NADPH-dependent P450 reductase (NPR) under CCl(4)-treated conditions. In HepG2 cells, intracellular lipid accumulation and its signaling were comparable to in vivo results. In order to elucidate the effect of the ER stress response itself, tunicamycin, an N-acetyl-glycosylation inhibitor, was injected into rats, followed by Oil Red O staining, lipid/triglyceride/cholesterol accumulation analysis, and examination of ApoB expression. Additionally, the ER stress response and upregulation of P450 2E1 were also confirmed in the tunicamycin-treated rats. All of the responses were similar to those seen with CCl(4). The P450 2E1 inhibitor diallyl sulphide (DAS), N-acetylcysteine (NAC), and reduced glutathione (GSH) antioxidants also regulated processes, including ApoB expression and lipid accumulation in CCl(4)-treated animals. In the presence of tunicamycin, DAS or NAC/GSH regulated all of the pathological phenomena with the exception of the ER stress response. In summary, CCl(4) induces liver steatosis, a process involving ER stress-induced P450 2E1 activation and ROS production.
authors: Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
authors: Geum-Hwa
authors: GH
authors: Lee
authors: Bidur
authors: B
authors: Bhandary
authors: Eun-Mi
authors: EM
authors: Lee
authors: Jin-Kyu
authors: JK
authors: Park
authors: Kyu-Shik
authors: KS
authors: Jeong
authors: In-Ki
authors: IK
authors: Kim
authors: Hyung-Ryong
authors: HR
authors: Kim
authors: Han-Jung
authors: HJ
authors: Chae
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1