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Title: Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4

Abstract

Objective: The accumulation of lipids in macrophages contributes to the development of atherosclerosis. Strategies to reduce lipid accumulation in macrophages may have therapeutic potential for preventing and treating atherosclerosis and cardiovascular complications. The antidiabetic drug metformin has been reported to reduce lipid accumulation in adipocytes. In this study, we examined the effects of metformin on lipid accumulation in macrophages and investigated the mechanisms involved. Methods and results: We observed that metformin significantly reduced palmitic acid (PA)-induced intracellular lipid accumulation in macrophages. Metformin promoted the expression of carnitine palmitoyltransferase I (CPT-1), while reduced the expression of fatty acid-binding protein 4 (FABP4) which was involved in PA-induced lipid accumulation. Quantitative real-time PCR showed that metformin regulates FABP4 expression at the transcriptional level. We identified forkhead transcription factor FOXO1 as a positive regulator of FABP4 expression. Inhibiting FOXO1 expression with FOXO1 siRNA significantly reduced basal and PA-induced FABP4 expression. Overexpression of wild-type FOXO1 and constitutively active FOXO1 significantly increased FABP4 expression, whereas dominant negative FOXO1 dramatically decreased FABP4 expression. Metformin reduced FABP4 expression by promoting FOXO1 nuclear exclusion and subsequently inhibiting its activity. Conclusions: Taken together, these results suggest that metformin reduces lipid accumulation in macrophages by repressing FOXO1-mediated FABP4 transcription. Thus, metforminmore » may have a protective effect against lipid accumulation in macrophages and may serve as a therapeutic agent for preventing and treating atherosclerosis in metabolic syndrome.« less

Authors:
 [1];  [2];  [2]; ;  [3];  [2];  [1];  [2];  [2];  [1];  [3];  [2]
  1. Qilu Hospital, Shandong University, Jinan, Shandong (China)
  2. (United States)
  3. Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (United States)
Publication Date:
OSTI Identifier:
22202391
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 393; Journal Issue: 1; Other Information: Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ARTERIOSCLEROSIS; CARNITINE; DRUGS; HEXADECANOIC ACID; LIPIDS; MACROPHAGES; POLYMERASE CHAIN REACTION; TRANSCRIPTION; TRANSCRIPTION FACTORS

Citation Formats

Song, Jun, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Ren, Pingping, Zhang, Lin, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Wang, Xing Li, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Chen, Li, Shen, Ying H., E-mail: hyshen@bcm.edu, and Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX. Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4. United States: N. p., 2010. Web. doi:10.1016/J.BBRC.2010.01.086.
Song, Jun, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Ren, Pingping, Zhang, Lin, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Wang, Xing Li, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Chen, Li, Shen, Ying H., E-mail: hyshen@bcm.edu, & Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX. Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4. United States. doi:10.1016/J.BBRC.2010.01.086.
Song, Jun, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Ren, Pingping, Zhang, Lin, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Wang, Xing Li, Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX, Chen, Li, Shen, Ying H., E-mail: hyshen@bcm.edu, and Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX. Fri . "Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4". United States. doi:10.1016/J.BBRC.2010.01.086.
@article{osti_22202391,
title = {Metformin reduces lipid accumulation in macrophages by inhibiting FOXO1-mediated transcription of fatty acid-binding protein 4},
author = {Song, Jun and Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX and Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX and Ren, Pingping and Zhang, Lin and Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX and Wang, Xing Li and Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX and Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX and Chen, Li and Shen, Ying H., E-mail: hyshen@bcm.edu and Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, TX},
abstractNote = {Objective: The accumulation of lipids in macrophages contributes to the development of atherosclerosis. Strategies to reduce lipid accumulation in macrophages may have therapeutic potential for preventing and treating atherosclerosis and cardiovascular complications. The antidiabetic drug metformin has been reported to reduce lipid accumulation in adipocytes. In this study, we examined the effects of metformin on lipid accumulation in macrophages and investigated the mechanisms involved. Methods and results: We observed that metformin significantly reduced palmitic acid (PA)-induced intracellular lipid accumulation in macrophages. Metformin promoted the expression of carnitine palmitoyltransferase I (CPT-1), while reduced the expression of fatty acid-binding protein 4 (FABP4) which was involved in PA-induced lipid accumulation. Quantitative real-time PCR showed that metformin regulates FABP4 expression at the transcriptional level. We identified forkhead transcription factor FOXO1 as a positive regulator of FABP4 expression. Inhibiting FOXO1 expression with FOXO1 siRNA significantly reduced basal and PA-induced FABP4 expression. Overexpression of wild-type FOXO1 and constitutively active FOXO1 significantly increased FABP4 expression, whereas dominant negative FOXO1 dramatically decreased FABP4 expression. Metformin reduced FABP4 expression by promoting FOXO1 nuclear exclusion and subsequently inhibiting its activity. Conclusions: Taken together, these results suggest that metformin reduces lipid accumulation in macrophages by repressing FOXO1-mediated FABP4 transcription. Thus, metformin may have a protective effect against lipid accumulation in macrophages and may serve as a therapeutic agent for preventing and treating atherosclerosis in metabolic syndrome.},
doi = {10.1016/J.BBRC.2010.01.086},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 393,
place = {United States},
year = {Fri Feb 26 00:00:00 EST 2010},
month = {Fri Feb 26 00:00:00 EST 2010}
}