TITLE

CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high‐fat diet‐induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway

AUTHOR(S)
Zuo, Anju; Zhao, Xiaoyu; Li, Tingting; Li, Jun; Lei, Shengyun; Chen, Jiying; Xu, Dan; Song, Chengxiang; Liu, Tianjiao; Li, Cuigang; Guo, Yuan
PUB. DATE
February 2020
SOURCE
Journal of Cellular & Molecular Medicine;Feb2020, Vol. 24 Issue 4, p2635
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
CTRP9 has been reported to regulate lipid metabolism and exert cardioprotective effects, yet its role in high‐fat diet (HFD)‐induced cardiac lipotoxicity and the underlying mechanisms remain unclear. In the current study, we established HFD‐induced obesity model in wild‐type (WT) or CTRP9 knockout (CTRP9‐KO) mice and palmitate‐induced lipotoxicity model in neonatal rat cardiac myocytes (NRCMs) to investigate the effects of CTRP9 on cardiac lipotoxicity. Our results demonstrated that the HFD‐fed CTRP9‐KO mice accentuated cardiac hypertrophy, fibrosis, endoplasmic reticulum (ER) stress‐initiated apoptosis and oxidative stress compared with the HFD‐fed WT mice. In vitro, CTRP9 treatment markedly alleviated palmitate‐induced oxidative stress and ER stress‐induced apoptosis in NRCMs in a dose‐dependent manner. Phosphorylated AMPK at Thr172 was reduced, and phosphorylated mammalian target of rapamycin (mTOR) was strengthened in the heart of the HFD‐fed CTRP9‐KO mice compared with the HFD‐fed control mice. In vitro, AMPK inhibitor compound C significantly abolished the effects of CTRP9 on the inhibition of the apoptotic pathway in palmitate‐treated NRCMs. In a further mechanistic study, CTRP9 enhanced expression of phosphorylated LKB1 at Ser428 and promoted LKB1 cytoplasmic localization. Besides, silencing of LKB1 gene by lentivirus significantly prohibited activation of AMPK by CTRP9 and partially eliminated the protective effect of CTRP9 on the cardiac lipotoxicity. These results indicate that CTRP9 exerted anti‐myocardial lipotoxicity properties and inhibited cardiac hypertrophy probably through the LKB1/AMPK signalling pathway.
ACCESSION #
141800971

 

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