R Han1, R Lai2, Q Ding1, Z Wang1, X Luo1, Y Zhang1, G Cui1, J He1, W Liu1, Y Chen3. 1. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, 200031, China. 2. Department of Biochemistry and Molecular Biology, Gannan Medical College, Ganzhou, Jiangxi, 341000, China. 3. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, 200031, China. ychen3@sibs.ac.cn.
Abstract
AIMS/HYPOTHESIS: In humans, one of the hallmarks of type 2 diabetes is a reduced plasma concentration of HDL and its major protein component, apolipoprotein A-I (APOA-I). However, it is unknown whether APOA-I directly protects against diabetes. The aim of this study was to characterise the functional role of APOA-I in glucose homeostasis. METHODS: The effects of APOA-I on phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase (ACC), glucose uptake and endocytosis were analysed in C2C12 myocytes. Glucose metabolism was investigated in Apoa-I knockout (Apoa-I (-/-)) mice. RESULTS: APOA-I was able to stimulate the phosphorylation of AMPK and ACC, and elevated glucose uptake in C2C12 myocytes. APOA-I could be endocytosed into C2C12 myotubes through a clathrin-dependent endocytotic process. Inhibition of endocytosis abrogated APOA-I-stimulated AMPK phosphorylation. In Apoa-I (-/-) mice, AMPK phosphorylation was reduced in skeletal muscle and liver, and expression of gluconeogenic enzymes was increased in liver. In addition, the Apoa-I (-/-) mice had increased fat content and compromised glucose tolerance. CONCLUSIONS/ INTERPRETATION: Our data indicate that APOA-I has a protective effect against diabetes via activation of AMPK. ApoA-I deletion in the mouse led to increased fat mass and impaired glucose tolerance.
AIMS/HYPOTHESIS: In humans, one of the hallmarks of type 2 diabetes is a reduced plasma concentration of HDL and its major protein component, apolipoprotein A-I (APOA-I). However, it is unknown whether APOA-I directly protects against diabetes. The aim of this study was to characterise the functional role of APOA-I in glucose homeostasis. METHODS: The effects of APOA-I on phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase (ACC), glucose uptake and endocytosis were analysed in C2C12 myocytes. Glucose metabolism was investigated in Apoa-I knockout (Apoa-I (-/-)) mice. RESULTS:APOA-I was able to stimulate the phosphorylation of AMPK and ACC, and elevated glucose uptake in C2C12 myocytes. APOA-I could be endocytosed into C2C12 myotubes through a clathrin-dependent endocytotic process. Inhibition of endocytosis abrogated APOA-I-stimulated AMPK phosphorylation. In Apoa-I (-/-) mice, AMPK phosphorylation was reduced in skeletal muscle and liver, and expression of gluconeogenic enzymes was increased in liver. In addition, the Apoa-I (-/-) mice had increased fat content and compromised glucose tolerance. CONCLUSIONS/ INTERPRETATION: Our data indicate that APOA-I has a protective effect against diabetes via activation of AMPK. ApoA-I deletion in the mouse led to increased fat mass and impaired glucose tolerance.
Authors: Liam R Brunham; Janine K Kruit; Terry D Pape; Jenelle M Timmins; Anne Q Reuwer; Zainisha Vasanji; Brad J Marsh; Brian Rodrigues; James D Johnson; John S Parks; C Bruce Verchere; Michael R Hayden Journal: Nat Med Date: 2007-02-18 Impact factor: 53.440
Authors: R Kozyraki; J Fyfe; M Kristiansen; C Gerdes; C Jacobsen; S Cui; E I Christensen; M Aminoff; A de la Chapelle; R Krahe; P J Verroust; S K Moestrup Journal: Nat Med Date: 1999-06 Impact factor: 53.440
Authors: S Morcillo; F Cardona; G Rojo-Martínez; I Esteva; M S Ruíz-de-Adana; F Tinahones; J M Gómez-Zumaquero; F Soriguer Journal: Diabet Med Date: 2005-06 Impact factor: 4.359
Authors: Brian G Drew; Noel H Fidge; Gabrielle Gallon-Beaumier; Bruce E Kemp; Bronwyn A Kingwell Journal: Proc Natl Acad Sci U S A Date: 2004-04-23 Impact factor: 11.205
Authors: Maria C de Beer; Lawrence W Castellani; Lei Cai; Arnold J Stromberg; Frederick C de Beer; Deneys R van der Westhuyzen Journal: J Lipid Res Date: 2004-01-16 Impact factor: 5.922
Authors: T Yamauchi; J Kamon; Y Minokoshi; Y Ito; H Waki; S Uchida; S Yamashita; M Noda; S Kita; K Ueki; K Eto; Y Akanuma; P Froguel; F Foufelle; P Ferre; D Carling; S Kimura; R Nagai; B B Kahn; T Kadowaki Journal: Nat Med Date: 2002-10-07 Impact factor: 53.440
Authors: Brian G Drew; Kerry-Anne Rye; Stephen J Duffy; Philip Barter; Bronwyn A Kingwell Journal: Nat Rev Endocrinol Date: 2012-01-24 Impact factor: 43.330
Authors: Maarit Lehti; Elizabeth Donelan; William Abplanalp; Omar Al-Massadi; Kirk M Habegger; Jon Weber; Chandler Ress; Johannes Mansfeld; Sonal Somvanshi; Chitrang Trivedi; Michaela Keuper; Teja Ograjsek; Cynthia Striese; Sebastian Cucuruz; Paul T Pfluger; Radhakrishna Krishna; Scott M Gordon; R A Gangani D Silva; Serge Luquet; Julien Castel; Sarah Martinez; David D'Alessio; W Sean Davidson; Susanna M Hofmann Journal: Circulation Date: 2013-10-29 Impact factor: 29.690