Inhibition of CYP4A Reduces Hepatic Endoplasmic Reticulum Stress and Features of Diabetes in Mice

Title
Inhibition of CYP4A Reduces Hepatic Endoplasmic Reticulum Stress and Features of Diabetes in Mice
Author(s)
박소영Edmond Changkyun Park[Edmond Changkyun Park]Seung II Kim[Seung II Kim]Yeonhee Hong[Yeonhee Hong]Jeong Won Hwang[Jeong Won Hwang]Gun Sik Cho[Gun Sik Cho]차혜나Jin-Kwan Han[Jin-Kwan Han]Chul-Ho Yun[Chul-Ho Yun]IK-Soon Jang[IK-Soon Jang]Zee-Won Lee[Zee-Won Lee]Jong-Soon Choi[Jong-Soon Choi]Soohyun Kim[Soohyun Kim]Gun-Hwa Kim[Gun-Hwa Kim]
Keywords
UNFOLDED PROTEIN RESPONSE; HEPG2 CELLS; ER-STRESS; NONALCOHOLIC STEATOHEPATITIS; CYTOCHROME-P450 2E1; LIPID-PEROXIDATION; INSULIN-RESISTANCE; INDUCED APOPTOSIS; LIVER-DISEASE; HIGH GLUCOSE
Issue Date
201410
Publisher
W B SAUNDERS CO-ELSEVIER INC
Citation
GASTROENTEROLOGY, v.147, no.4, pp.860 - 869
Abstract
BACKGROUND & AIMS: 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.
URI
http://hdl.handle.net/YU.REPOSITORY/30614http://dx.doi.org/10.1053/j.gastro.2014.06.039
ISSN
0016-5085
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의과대학 > 생리학교실 > Articles
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