title: Inhibition of CYP4A reduces hepatic endoplasmic reticulum stress and features of diabetes in mice.
abstract: OBJECTIVE
  Endoplasmic reticulum (ER) stress is implicated in the development of type 2 diabetes mellitus. ER stress activates the unfolded protein response pathway, which contributes to apoptosis and insulin resistance. We investigated the roles of cytochrome P450 4A (CYP4A) in the regulation of hepatic ER stress, insulin resistance, and the development of diabetes in mice.
  
  
  METHODS
  We used mass spectrometry to compare levels of CYP450 proteins in livers from C57BL/6J and C57BL/KsJ-db/db (db/db) mice; findings were confirmed by immunoblot and real-time PCR analyses. To create a model of diet-induced diabetes, C57BL/6J mice were placed on high-fat diets. Mice were given intraperitoneal injections of an inhibitor (HET0016) or an inducer (clofibrate) of CYP4A, or tail injections of small hairpin RNAs against CYP4A messenger RNA; liver tissues were collected and analyzed for ER stress, insulin resistance, and apoptosis. The effect of HET0016 and CYP4A knockdown also were analyzed in HepG2 cells.
  
  
  RESULTS
  Levels of the CYP4A isoforms were highly up-regulated in livers of db/db mice compared with C57BL/6J mice. Inhibition of CYP4A in db/db and mice on high-fat diets reduced features of diabetes such as insulin hypersecretion, hepatic steatosis, and increased glucose tolerance. CYP4A inhibition reduced levels of ER stress, insulin resistance, and apoptosis in the livers of diabetic mice; it also restored hepatic functions. Inversely, induction of CYP4A accelerated ER stress, insulin resistance, and apoptosis in livers of db/db mice.
  
  
  CONCLUSIONS
  CYP4A proteins are up-regulated in livers of mice with genetically induced and diet-induced diabetes. Inhibition of CYP4A in mice reduces hepatic ER stress, apoptosis, insulin resistance, and steatosis. Strategies to reduce levels or activity of CYP4A proteins in liver might be developed for treatment of patients with type 2 diabetes.
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Edmond Changkyun
authors.initials: EC
authors.lastname: Park
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Seung Il
authors.initials: SI
authors.lastname: Kim
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Yeonhee
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Hwang
authors.affiliation: Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Gun-Sik
authors.initials: GS
authors.lastname: Cho
authors.affiliation: Department of Physiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
authors.forename: Hye-Na
authors.initials: HN
authors.lastname: Cha
authors.affiliation: Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
authors.forename: Jin-Kwan
authors.initials: JK
authors.lastname: Han
authors.affiliation: School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Yun
authors.affiliation: Department of Physiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Ik-Soon
authors.initials: IS
authors.lastname: Jang
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea.
authors.forename: Zee-Won
authors.initials: ZW
authors.lastname: Lee
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea; Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Biofabula, Daejeon, Republic of Korea.
authors.forename: Soohyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Life Science, Korea Basic Science Institute, Daejeon, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea. Electronic address: genegkh@kbsi.re.kr.
authors.forename: Gun-Hwa
authors.initials: GH
authors.lastname: Kim
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D003920:Diabetes Mellitus / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D040901:Proteomics / Q000379:methods; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D000578:Amidines; D001786:Blood Glucose; D004791:Enzyme Inhibitors; C000708209:HET0016; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D042926:Cytochrome P-450 CYP4A
keywords: Mouse Model; Obesity; Proteomic Analysis; UPR