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Chronic HMGCR/HMG-CoA Reductase Inhibitor Treatment Contributes to Dysglycemia by Upregulating Hepatic Gluconeogenesis through Autophagy Induction

Authors
 Hye Jin Wang  ;  , Jae Yeo Park  ;  Eun Seok Kang  ;  Hyangkyu Lee  ;  Young-Bum Kim  ;  Bong Soo Cha  ;  Mijin Yun  ;  Myung-Shik Lee  ;  Kyu Yeon Hur  ;  Chul Hoon Kim  ;  Eun Yeong Choe  ;  Obin Kwon 
Citation
 Autophagy, Vol.11(11) : 2089-2101, 2015 
Journal Title
 Autophagy 
ISSN
 1554-8627 
Issue Date
2015
Abstract
Statins (HMGCR/HMG-CoA reductase [3-hydroxy-3-methylglutaryl-CoA reductase] inhibitors) are widely used to lower blood cholesterol levels but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanism underlying diabetogenic effects remains to be elucidated. Here we show that statins significantly increase the expression of key gluconeogenic enzymes (such as G6PC [glucose-6-phosphatase] and PCK1 (phosphoenolpyruvate carboxykinase 1 [soluble]) in vitro and in vivo and promote hepatic glucose output. Statin treatment activates autophagic flux in HepG2 cells. Acute suppression of autophagy with lysosome inhibitors in statin treated HepG2 cells reduced gluconeogenic enzymes expression and glucose output. Importantly, the ability of statins to increase gluconeogenesis was impaired when ATG7 was deficient and BECN1 was absent, suggesting that autophagy plays a critical role in the diabetogenic effects of statins. Moreover autophagic vacuoles and gluconeogenic genes expression in the liver of diet-induced obese mice were increased by statins, ultimately leading to elevated hepatic glucose production, hyperglycemia, and insulin resistance. Together, these data demonstrate that chronic statin therapy results in insulin resistance through the activation of hepatic gluconeogenesis, which is tightly coupled to hepatic autophagy. These data further contribute to a better understanding of the diabetogenic effects of stains in the context of insulin resistance.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/141817
DOI
10.1080/15548627.2015.1091139
Appears in Collections:
1. Journal Papers (연구논문) > 3. College of Nursing (간호대학) > Dept. of Nursing (간호학과)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부)
Yonsei Authors
강은석(Kang, Eun Seok) ; 김철훈(Kim, Chul Hoon) ; 윤미진(Yun, Mi Jin) ; 이명식(Lee, Myung Shik) ; 이향규(Lee, Hyang Kyu) ; 차봉수(Cha, Bong Soo) ; 허규연(Hur, Kyu Yeon)
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http://www.tandfonline.com/doi/full/10.1080/15548627.2015.1091139#.VlZkSHIw-Uk
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