title: Effect of BI-1 on insulin resistance through regulation of CYP2E1.
abstract: Diet-induced obesity is a major contributing factor to the progression of hepatic insulin resistance. Increased free fatty acids in liver enhances endoplasmic reticulum (ER) stress and production of reactive oxygen species (ROS), both are directly responsible for dysregulation of hepatic insulin signaling. BI-1, a recently studied ER stress regulator, was examined to investigate its association with ER stress and ROS in insulin resistance models. To induce obesity and insulin resistance, BI-1 wild type and BI-1 knock-out mice were fed a high-fat diet for 8 weeks. The BI-1 knock-out mice had hyperglycemia, was associated with impaired glucose and insulin tolerance under high-fat diet conditions. Increased activity of NADPH-dependent CYP reductase-associated cytochrome p450 2E1 (CYP2E1) and exacerbation of ER stress in the livers of BI-1 knock-out mice was also observed. Conversely, stable expression of BI-1 in HepG2 hepatocytes was shown to reduce palmitate-induced ER stress and CYP2E1-dependent ROS production, resulting in the preservation of intact insulin signaling. Stable expression of CYP2E1 led to increased ROS production and dysregulation of insulin signaling in hepatic cells, mimicking palmitate-mediated hepatic insulin resistance. We propose that BI-1 protects against obesity-induced hepatic insulin resistance by regulating CYP2E1 activity and ROS production.
authors: Department of Pharmacology and New Drug Development Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea.
authors: Geum-Hwa
authors: GH
authors: Lee
authors: Division of Life Sciences, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 136-713, Republic of Korea.|Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, Republic of Korea.
authors: Kyoung-Jin
authors: KJ
authors: Oh
authors: Department of Dental Pharmacology and Wonkwang Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, 570-749, Republic of Korea.
authors: Hyung-Ryong
authors: HR
authors: Kim
authors: Division of Life Sciences, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 136-713, Republic of Korea.
authors: Hye-Sook
authors: HS
authors: Han
authors: Department of Pharmacology and New Drug Development Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea.
authors: Hwa-Young
authors: HY
authors: Lee
authors: Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, 700-721, Republic of Korea.
authors: Keun-Gyu
authors: KG
authors: Park
authors: Laboratory Animal Resource Center, KRIBB, Ochang-eup, 363-883, Republic of Korea.
authors: Ki-Hoan
authors: KH
authors: Nam
authors: Division of Life Sciences, Korea University, 145 Anam-Ro, Seongbuk-Gu, Seoul, 136-713, Republic of Korea.
authors: Seung-Hoi
authors: SH
authors: Koo
authors: Department of Pharmacology and New Drug Development Institute, Medical School, Chonbuk National University, Jeonju, 561-181, Republic of Korea.
authors: Han-Jung
authors: HJ
authors: Chae
mesh_terms: D000818:Animals; D001786:Blood Glucose; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress; D015971:Gene Expression Regulation, Enzymologic; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000201:enzymology / Q000209:etiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C490015:Tmbim6 protein, mouse; D019392:Cytochrome P-450 CYP2E1; C000617651:cytochrome P-450 2E1, mouse