5-LO inhibition ameliorates palmitic acid-induced ER stress, oxidativestress and insulin resistance via AMPK activation in murine myotubes

Collection with item attached
2017
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/473449.do
DOI
10.1038/s41598-017-05346-5
Title
5-LO inhibition ameliorates palmitic acid-induced ER stress, oxidativestress and insulin resistance via AMPK activation in murine myotubes
Description
This research was supported by Basic Science Research Program throughthe National Research Foundation of Korea (NRF) funded by the Ministryof Education (Grant no. 2015R1D1A1A01058235) and the Korean HealthTechnology R& D Project of the Korean Health Industry DevelopmentInstitute (KHIDI) funded by the Korean Ministry of Health & Welfare(Grant no. HI14C1135).
abstract
Leukotriene B4 (LTB4) production via the 5-lipoxygenase (5-LO) pathway contributes to the development of insulin resistance in adipose and hepatic tissues, but the role of LTB4 in skeletal muscle is relatively unknown. Here, the authors investigated the role of LTB4 in C2C12 myotubes in palmitic acid (PA)-induced ER stress, inflammation and insulin resistance. PA (750 mu M) evoked lipotoxicity (ER stress, oxidative stress, inflammation and insulin resistance) in association with LTB4 production. 5-LO inhibition reduced all the lipotoxic effects induced by PA. On the other hand, PA did not induce cysteinyl leukotrienes (CysLTs), which themselves had no effect on ER stress and inflammation. The beneficial effects of 5-LO suppression from PA-induced lipotoxicity were related with AMPK activation. In ob/ob mice, once daily oral administration of zileuton (50, 100 mg/kg) for 5 weeks improved insulin resistance, increased AMPK phosphorylation, and reduced LTB4 and ER stress marker expression in skeletal muscle. These results show that 5-LO inhibition by either zileuton or 5-LO siRNA protects C2C12 myotubes from PA-induced lipotoxicity, at least partly via AMPK activation, and suggest that the in vivo insulin-sensitizing effects of zileuton are in part attributable to its direct action on skeletal muscle via LTB4 downregulation followed by AMPK activation.
provenance
Made available in Cube on 2018-09-28T10:19:52Z (GMT). No. of bitstreams: 0
language
English
author
Kwak, Hyun Jeong
Choi, Hye-Eun
Cheon, Hyae Gyeong
accessioned
2018-09-28T10:19:52Z
available
2018-09-28T10:19:52Z
issued
2017
citation
SCIENTIFIC REPORTS(7)
issn
2045-2322
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/473449.do
Funder
보건복지부
Funding Program
연구중심병원육성
Project ID
1465023485
Jurisdiction
Rep.of Korea
Project Name
Establishment of platform technology and target validation research for the development of innovative therapeutics of metabolic diseases
rights
openAccess
type
article


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