The online version of this article (doi:10.1186/1475-2840-11-72) contains supplementary material, which is available to authorized users.
Dr. Masana has provided lectures, consultancies and expert testimony to several pharmaceutical companies involved in lipid metabolism, such as Merk Sharp & Dohme, Roche, Esteve, Recordati and Kowa.
GA conducted the experimental work with contributions from JG, GA, PS, MH, AC, JG and LM contributed to method development, establishment of cell lines, experimental design and data interpretation. GA, JG and LM wrote the paper. All authors read and approved the final paper.
Recent studies have shown that fatty acid-binding protein 4 (FABP4) plasma levels are associated with impaired endothelial function in type 2 diabetes (T2D). In this work, we analysed the effect of FABP4 on the insulin-mediated nitric oxide (NO) production by endothelial cells in vitro.
In human umbilical vascular endothelial cells (HUVECs), we measured the effects of FABP4 on the insulin-mediated endothelial nitric oxide synthase (eNOS) expression and activation and on NO production. We also explored the impact of exogenous FABP4 on the insulin-signalling pathway (insulin receptor substrate 1 (IRS1) and Akt).
We found that eNOS expression and activation and NO production are significantly inhibited by exogenous FABP4 in HUVECs. FABP4 induced an alteration of the insulin-mediated eNOS pathway by inhibiting IRS1 and Akt activation. These results suggest that FABP4 induces endothelial dysfunction by inhibiting the activation of the insulin-signalling pathway resulting in decreased eNOS activation and NO production.
These findings provide a mechanistic linkage between FABP4 and impaired endothelial function in diabetes, which leads to an increased cardiovascular risk.
Authors’ original file for figure 112933_2012_549_MOESM1_ESM.tiff
Authors’ original file for figure 212933_2012_549_MOESM2_ESM.tiff
Authors’ original file for figure 312933_2012_549_MOESM3_ESM.tiff
Authors’ original file for figure 412933_2012_549_MOESM4_ESM.tiff
Authors’ original file for figure 512933_2012_549_MOESM5_ESM.jpeg
Authors’ original file for figure 612933_2012_549_MOESM6_ESM.jpeg
Authors’ original file for figure 712933_2012_549_MOESM7_ESM.jpeg
Authors’ original file for figure 812933_2012_549_MOESM8_ESM.jpeg
Authors’ original file for figure 912933_2012_549_MOESM9_ESM.jpeg
Cabre A, Lazaro I, Girona J, Manzanares JM, Marimon F, Plana N, Heras M, Masana L: Fatty acid binding protein 4 is increased in metabolic syndrome and with thiazolidinedione treatment in diabetic patients. Atherosclerosis. 2007, 195 (1): e150-e158. 10.1016/j.atherosclerosis.2007.04.045. CrossRefPubMed
Coll B, Cabre A, Alonso-Villaverde C, Lazaro I, Aragones G, Parra S, Girona J, Masana L: The fatty acid binding protein-4 (FABP4) is a strong biomarker of metabolic syndrome and lipodystrophy in HIV-infected patients. Atherosclerosis. 2008, 199 (1): 147-153. 10.1016/j.atherosclerosis.2007.09.032. CrossRefPubMed
Xu A, Tso AW, Cheung BM, Wang Y, Wat NM, Fong CH, Yeung DC, Janus ED, Sham PC, Lam KS: Circulating adipocyte-fatty acid binding protein levels predict the development of the metabolic syndrome: a 5-year prospective study. Circulation. 2007, 115 (12): 1537-1543. 10.1161/CIRCULATIONAHA.106.647503. CrossRefPubMed
Hong J, Gu W, Zhang Y, Yan Q, Dai M, Shi J, Zhai Y, Wang W, Li X, Ning G: Different association of circulating levels of adipocyte and epidermal fatty acid-binding proteins with metabolic syndrome and coronary atherosclerosis in Chinese adults. Atherosclerosis. 2011, 217 (1): 194-200. 10.1016/j.atherosclerosis.2011.03.002. CrossRefPubMed
Doi M, Miyoshi T, Hirohata S, Nakamura K, Usui S, Takeda K, Iwamoto M, Kusachi S, Kusano K, Ito H: Association of increased plasma adipocyte fatty acid-binding protein with coronary artery disease in non-elderly men. Cardiovasc Diabetol. 2011, 10: 44-10.1186/1475-2840-10-44. PubMedCentralCrossRefPubMed
Lamounier-Zepter V, Look C, Alvarez J, Christ T, Ravens U, Schunck W, Ehrhart-Bornstein M, Bornstein SR, Morano I: Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: a new link between obesity and heart disease. Circ Res. 2009, 105 (4): 326-334. 10.1161/CIRCRESAHA.109.200501. CrossRefPubMed
Lan H, Cheng CC, Kowalski TJ, Pang L, Shan L, Chuang CC, Jackson J, Rojas-Triana A, Bober L, Liu L, Voigt J, Orth P, Yang X, Shipps GW, Hedrick JA: Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity. J Lipid Res. 2011, 52 (4): 646-656. 10.1194/jlr.M012757. PubMedCentralCrossRefPubMed
Hresko RC, Hoffman RD, Flores-Riveros JR, Lane MD: Insulin receptor tyrosine kinase-catalyzed phosphorylation of 422(aP2) protein. Substrate activation by long-chain fatty acid. J Biol Chem. 1990, 265 (34): 21075-21085. PubMed
Nielsen SU, Spener F: Fatty acid-binding protein from rat heart is phosphorylated on Tyr19 in response to insulin stimulation. J Lipid Res. 1993, 34 (8): 1355-1366. PubMed
Karbek B, Ozbek M, Bozkurt NC, Ginis Z, Güngünes A, Ünsal IÖ, Cakal E, Delibası T: Heart-type fatty acid binding protein (H-FABP): relationship with arterial intima-media thickness and role as diagnostic marker for atherosclerosis in patients with ımpaired glucose metabolism. Cardiovasc Diabetol. 2011, 10: 37-10.1186/1475-2840-10-37. PubMedCentralCrossRefPubMed
- Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II