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Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2

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 diab... Full description

Journal Title: Nature 2007-07-21, Vol.447 (7147), p.959-965
Main Author: Makowski, Liza
Other Authors: Hotamisligil, Gökhan S , Tuncman, Gürol , Görgün, Cem Z , Fazio, Sergio , Parker, Rex A , Kono, Keita , Robl, Jeffrey A , Atsumi, Genichi , Sulsky, Richard , Babaev, Vladimir R , Furuhashi, Masato , Linton, MacRae F , Vaillancourt, Eric
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: London: Nature Publishing
ID: ISSN: 0028-0836
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4076119
title: Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2
format: Article
creator:
  • Makowski, Liza
  • Hotamisligil, Gökhan S
  • Tuncman, Gürol
  • Görgün, Cem Z
  • Fazio, Sergio
  • Parker, Rex A
  • Kono, Keita
  • Robl, Jeffrey A
  • Atsumi, Genichi
  • Sulsky, Richard
  • Babaev, Vladimir R
  • Furuhashi, Masato
  • Linton, MacRae F
  • Vaillancourt, Eric
subjects:
  • Adipocytes - drug effects
  • Adipocytes - metabolism
  • Adipose Tissue - cytology
  • Adipose Tissue - drug effects
  • Adipose Tissue - metabolism
  • Animals
  • Apolipoproteins E - deficiency
  • Apolipoproteins E - genetics
  • Article
  • Atherosclerosis
  • Atherosclerosis (general aspects, experimental research)
  • Atherosclerosis - drug therapy
  • Atherosclerosis - genetics
  • Atherosclerosis - metabolism
  • beverages
  • Binding proteins
  • Biological and medical sciences
  • Biphenyl Compounds - metabolism
  • Blood and lymphatic vessels
  • Cardiology. Vascular system
  • Care and treatment
  • Cell Line
  • Cholesterol - metabolism
  • Control
  • Diabetes
  • Diabetes Mellitus - drug therapy
  • Diabetes Mellitus - genetics
  • Diabetes Mellitus - metabolism
  • Diabetes. Impaired glucose tolerance
  • Endocrine pancreas. Apud cells (diseases)
  • Endocrinopathies
  • Etiopathogenesis. Screening. Investigations. Target tissue resistance
  • Fatty Acid-Binding Proteins - antagonists & inhibitors
  • Fatty Acid-Binding Proteins - metabolism
  • food
  • Humans
  • Inflammation - metabolism
  • Inhibitors
  • Lipids
  • Liver - drug effects
  • Liver - metabolism
  • Macrophages
  • Macrophages - drug effects
  • Macrophages - metabolism
  • Medical sciences
  • Metabolic diseases
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Miscellaneous
  • Models, Biological
  • Obesity - genetics
  • Obesity - metabolism
  • Other metabolic disorders
  • Pathways
  • Physiological aspects
  • Proteins
  • Pyrazoles - metabolism
ispartof: Nature, 2007-07-21, Vol.447 (7147), p.959-965
description: 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.
language: eng
source:
identifier: ISSN: 0028-0836
fulltext: no_fulltext
issn:
  • 0028-0836
  • 1476-4687
  • 1476-4679
url: Link


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titleTreatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2
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creatorcontribMakowski, Liza ; Hotamisligil, Gökhan S ; Tuncman, Gürol ; Görgün, Cem Z ; Fazio, Sergio ; Parker, Rex A ; Kono, Keita ; Robl, Jeffrey A ; Atsumi, Genichi ; Sulsky, Richard ; Babaev, Vladimir R ; Furuhashi, Masato ; Linton, MacRae F ; Vaillancourt, Eric
descriptionAdipocyte 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.
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languageeng
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subjectAdipocytes - drug effects ; Adipocytes - metabolism ; Adipose Tissue - cytology ; Adipose Tissue - drug effects ; Adipose Tissue - metabolism ; Animals ; Apolipoproteins E - deficiency ; Apolipoproteins E - genetics ; Article ; Atherosclerosis ; Atherosclerosis (general aspects, experimental research) ; Atherosclerosis - drug therapy ; Atherosclerosis - genetics ; Atherosclerosis - metabolism ; beverages ; Binding proteins ; Biological and medical sciences ; Biphenyl Compounds - metabolism ; Blood and lymphatic vessels ; Cardiology. Vascular system ; Care and treatment ; Cell Line ; Cholesterol - metabolism ; Control ; Diabetes ; Diabetes Mellitus - drug therapy ; Diabetes Mellitus - genetics ; Diabetes Mellitus - metabolism ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Fatty Acid-Binding Proteins - antagonists & inhibitors ; Fatty Acid-Binding Proteins - metabolism ; food ; Humans ; Inflammation - metabolism ; Inhibitors ; Lipids ; Liver - drug effects ; Liver - metabolism ; Macrophages ; Macrophages - drug effects ; Macrophages - metabolism ; Medical sciences ; Metabolic diseases ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Miscellaneous ; Models, Biological ; Obesity - genetics ; Obesity - metabolism ; Other metabolic disorders ; Pathways ; Physiological aspects ; Proteins ; Pyrazoles - metabolism
ispartofNature, 2007-07-21, Vol.447 (7147), p.959-965
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1Hotamisligil, Gökhan S
2Tuncman, Gürol
3Görgün, Cem Z
4Fazio, Sergio
5Parker, Rex A
6Kono, Keita
7Robl, Jeffrey A
8Atsumi, Genichi
9Sulsky, Richard
10Babaev, Vladimir R
11Furuhashi, Masato
12Linton, MacRae F
13Vaillancourt, Eric
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0Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2
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descriptionAdipocyte 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.
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0Adipocytes - drug effects
1Adipocytes - metabolism
2Adipose Tissue - cytology
3Adipose Tissue - drug effects
4Adipose Tissue - metabolism
5Animals
6Apolipoproteins E - deficiency
7Apolipoproteins E - genetics
8Article
9Atherosclerosis
10Atherosclerosis (general aspects, experimental research)
11Atherosclerosis - drug therapy
12Atherosclerosis - genetics
13Atherosclerosis - metabolism
14beverages
15Binding proteins
16Biological and medical sciences
17Biphenyl Compounds - metabolism
18Blood and lymphatic vessels
19Cardiology. Vascular system
20Care and treatment
21Cell Line
22Cholesterol - metabolism
23Control
24Diabetes
25Diabetes Mellitus - drug therapy
26Diabetes Mellitus - genetics
27Diabetes Mellitus - metabolism
28Diabetes. Impaired glucose tolerance
29Endocrine pancreas. Apud cells (diseases)
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32Fatty Acid-Binding Proteins - antagonists & inhibitors
33Fatty Acid-Binding Proteins - metabolism
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44Medical sciences
45Metabolic diseases
46Mice
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48Mice, Mutant Strains
49Miscellaneous
50Models, Biological
51Obesity - genetics
52Obesity - metabolism
53Other metabolic disorders
54Pathways
55Physiological aspects
56Proteins
57Pyrazoles - metabolism
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4Fazio, Sergio
5Parker, Rex A
6Kono, Keita
7Robl, Jeffrey A
8Atsumi, Genichi
9Sulsky, Richard
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11Furuhashi, Masato
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titleTreatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2
authorMakowski, Liza ; Hotamisligil, Gökhan S ; Tuncman, Gürol ; Görgün, Cem Z ; Fazio, Sergio ; Parker, Rex A ; Kono, Keita ; Robl, Jeffrey A ; Atsumi, Genichi ; Sulsky, Richard ; Babaev, Vladimir R ; Furuhashi, Masato ; Linton, MacRae F ; Vaillancourt, Eric
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1Adipocytes - metabolism
2Adipose Tissue - cytology
3Adipose Tissue - drug effects
4Adipose Tissue - metabolism
5Animals
6Apolipoproteins E - deficiency
7Apolipoproteins E - genetics
8Article
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10Atherosclerosis (general aspects, experimental research)
11Atherosclerosis - drug therapy
12Atherosclerosis - genetics
13Atherosclerosis - metabolism
14beverages
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16Biological and medical sciences
17Biphenyl Compounds - metabolism
18Blood and lymphatic vessels
19Cardiology. Vascular system
20Care and treatment
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22Cholesterol - metabolism
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26Diabetes Mellitus - genetics
27Diabetes Mellitus - metabolism
28Diabetes. Impaired glucose tolerance
29Endocrine pancreas. Apud cells (diseases)
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33Fatty Acid-Binding Proteins - metabolism
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56Proteins
57Pyrazoles - metabolism
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1Hotamisligil, Gökhan S
2Tuncman, Gürol
3Görgün, Cem Z
4Fazio, Sergio
5Parker, Rex A
6Kono, Keita
7Robl, Jeffrey A
8Atsumi, Genichi
9Sulsky, Richard
10Babaev, Vladimir R
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12Linton, MacRae F
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7Robl, Jeffrey A
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0Present address: Clinical Molecular Biology, Teikyo University, Kanagawa 199-0195, Japan.
1Present address: Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina 27704, USA.
abstractAdipocyte 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.
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