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Jens Lagerstedt

Associate professor

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Site-specific glycations of apolipoprotein A-I lead to differentiated functional effects on lipid-binding and on glucose metabolism

Author

  • Joan Domingo-Espín
  • Oktawia Nilsson
  • Katja Bernfur
  • Rita Del Giudice
  • Jens O. Lagerstedt

Summary, in English

Prolonged hyperglycemia in poorly controlled diabetes leads to an increase in reactive glucose metabolites that covalently modify proteins by non-enzymatic glycation reactions. Apolipoprotein A-I (apoA-I) of high-density lipoprotein (HDL) is one of the proteins that becomes glycated in hyperglycemia. The impact of glycation on apoA-I protein structure and function in lipid and glucose metabolism were investigated. ApoA-I was chemically glycated by two different glucose metabolites (methylglyoxal and glycolaldehyde). Synchrotron radiation and conventional circular dichroism spectroscopy were used to study apoA-I structure and stability. The ability to bind lipids was measured by lipid-clearance assay and native gel analysis, and cholesterol efflux was measured by using lipid-laden J774 macrophages. Diet induced obese mice with established insulin resistance, L6 rat and C2C12 mouse myocytes, as well as INS-1E rat insulinoma cells, were used to determine in vivo and in vitro glucose uptake and insulin secretion. Site-specific, covalent modifications of apoA-I (lysines or arginines) led to altered protein structure, reduced lipid binding capability and a reduced ability to catalyze cholesterol efflux from macrophages, partly in a modification-specific manner. The stimulatory effects of apoA-I on the in vivo glucose clearance were negatively affected when apoA-I was modified with methylglyoxal, but not with glycolaldehyde. The in vitro data showed that both glucose uptake in muscle cells and insulin secretion from beta cells were affected. Taken together, glycation modifications impair the apoA-I protein functionality in lipid and glucose metabolism, which is expected to have implications for diabetes patients with poorly controlled blood glucose.

Department/s

  • Medical Protein Science
  • Biochemistry and Structural Biology
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2018-01-01

Language

English

Pages

2822-2834

Publication/Series

Biochimica et Biophysica Acta - Molecular Basis of Disease

Volume

1864

Issue

9

Document type

Journal article

Publisher

Elsevier

Topic

  • Biochemistry and Molecular Biology

Keywords

  • apoA-I
  • Diabetes
  • Glucose metabolism
  • Glycation
  • HDL
  • High-density lipoprotein

Status

Published

Research group

  • Medical Protein Science

ISBN/ISSN/Other

  • ISSN: 0925-4439