Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism

Diabetologia. 2007 Sep;50(9):1960-1968. doi: 10.1007/s00125-007-0752-7. Epub 2007 Jul 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Apolipoprotein A-I / pharmacology*
  • Cell Line
  • Deoxyglucose / metabolism
  • Enzyme Activation / drug effects
  • Glucose / metabolism*
  • Mice
  • Multienzyme Complexes / drug effects
  • Multienzyme Complexes / metabolism*
  • Muscle Cells / drug effects
  • Muscle Cells / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*

Substances

  • Apolipoprotein A-I
  • Multienzyme Complexes
  • Deoxyglucose
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glucose