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


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.
Song
Jun
J
Qilu Hospital, Shandong University, Jinan, Shandong, China.
Ren
Pingping
P
Zhang
Lin
L
Wang
Xing Li
XL
Chen
Li
L
Shen
Ying H
YH
D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D002334:Carnitine O-Palmitoyltransferase / Q000096:biosynthesis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D050556:Fatty Acid-Binding Proteins / Q000235:genetics*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D019308:Palmitic Acid / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation
C493410:FABP4 protein, human; C085126:FOXO1 protein, human; D050556:Fatty Acid-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D019308:Palmitic Acid; D008687:Metformin; D002334:Carnitine O-Palmitoyltransferase