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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
Keywords
HMG-CoA reductase inhibitor ; autophagy ; diabetes ; gluconeogenesis ; statin
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.
Full Text
http://www.tandfonline.com/doi/full/10.1080/15548627.2015.1091139#.VlZkSHIw-Uk
DOI
10.1080/15548627.2015.1091139
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
3. College of Nursing (간호대학) > Dept. of Nursing (간호학과) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Kim, Chul Hoon(김철훈) ORCID logo https://orcid.org/0000-0002-7360-429X
Yun, Mijin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
Lee, Hyang Kyu(이향규) ORCID logo https://orcid.org/0000-0002-0821-6020
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
Hur, Kyu Yeon(허규연)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/141817
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