Our lab focuses on the biological role of lipid chaperones called fatty acid-binding proteins (FABPs), which bind to lipids as well as other endogenous structures and dictate their composition, partitioning, and function in cells. Our research has been focused on the role of the two FABP isoforms expressed in adipocytes and macrophages, FABP4 and FABP5 (also known as aP2 and mal1). We have developed several mouse models that are deficient in aP2 and mal1, and found that these animals are protected from some of the most detrimental effects of high dietary levels of fatty acids, including obesity, insulin resistance, type 2 diabetes, fatty liver and cardiovascular disease. Obesity has also been recognized as a risk factor for asthma and certain cancers and FABP4-deficient mice exhibit resistance to allergic airway inflammation, as well as ovarian cancer, raising the possibility that this molecule plays a very broad role in a cluster of chronic metabolic diseases.
Suggested Readings:
Cao H, Sekiya M, Ertunc ME, Burak MF, Mayers JR, White A, Inouye K, Rickey LM, Ercal BC, Furuhashi M, Tuncman G,Hotamışlıgil GS. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab., 2013 May 7;17(5):768-78. Abstract | PDF
Ertunc ME, Sikkeland J, Fenaroli F, Griffiths G, Daniels MP, Cao H, Saatcioglu F, Hotamışlıgil GS. Secretion of fatty acid binding protein aP2 from adipocytes through a non-classical pathway in response to adipocyte lipase activity. Journal of Lipid Research 2014 December 22 doi: 10.1194/jlr.M055798. Abstract | PDF
Charles KN, Li M, Engin F, Arruda AP, Inouye K, Hotamışlıgil GS. Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins. Cell Reports. 2017 Oct; DOI:10.1016/j.celrep.2017.09.051.Abstract
Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, MacRae FL, Sulsky R, Robl JA, Parker RA, Hotamışlıgil GS. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature, 2007, 447:959-965. Abstract |PDF
Hotamışlıgil GS, Bernlohr DA. Metabolic functions of FABPs—mechanisms and therapeutic implications. Nature Reviews Endocrinology 2015 August 11 doi:10.1038/nrendo.2015.122. Abstract | PDF
Inouye KE, Prentice KJ, Lee A, Wang ZB, Dominguez-Gonzalez C, Chen MX, Riveros JK, Burak MF, Lee GY, Hotamışlıgil GS. Endothelial-derived FABP4 constitutes the majority of basal circulating hormone and regulates lipolysis-driven insulin secretion. JCI Insight. 2023 Jul 24;8(14):e164642. doi: 10.1172/jci.insight.164642.
Prentice KJ, Saksi J, Robertson LT, Lee GY, Inouye KE, Eguchi K, Lee A, Cakici O, Otterbeck E, Cedillo P, Achenbach P, Ziegler AG, Calay ES, Engin F, Hotamisligil GS. A hormone complex of FABP4 and nucleoside kinases regulates islet function. Nature. 2021 Dec;600(7890):720-726. doi: 10.1038/s41586-021-04137-3.
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