Treatment of Diabetes and Atherosclerosis by Inhibiting Fatty-Acid-Binding Protein aP2

Nature. 2007 Jun 21;447(7147):959-65. doi: 10.1038/nature05844. Epub 2007 Jun 6.

Abstract

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue / cytology
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Biphenyl Compounds / metabolism
  • Cell Line
  • Cholesterol / metabolism
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism
  • Fatty Acid-Binding Proteins / antagonists & inhibitors*
  • Fatty Acid-Binding Proteins / metabolism
  • Humans
  • Inflammation / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Models, Biological
  • Obesity / genetics
  • Obesity / metabolism
  • Pyrazoles / metabolism

Substances

  • 2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid
  • Apolipoproteins E
  • Biphenyl Compounds
  • Fabp4 protein, mouse
  • Fatty Acid-Binding Proteins
  • Pyrazoles
  • Cholesterol