Lipid and Nutrient Biology, Trafficking, Signaling and Chaperones in Metabolic Regulation

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Reversal of atherosclerosis in FABP-deficiency

The nutrient content of a diet has profound influence on a number of vital physiological pathways. Furthermore, a strong link exists between dietary trends and a number of common diseases such as cancer, diabetes and atherosclerosis. Although a major emphasis on diabetes research is the dysregulation of glucose metabolism, equally important are the characteristic alterations in lipid metabolism. However, it has been challenging to determine the mechanisms of lipid and nutrient actions and their specific involvement with critical regulatory or toxic pathways. Our work in this area is in two major pillars:

Lipid Binding Proteins:

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Fatty acid binding protein in adipocytes

One way we approach the molecular basis of these interactions is by focusing 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.

Our mechanistic studies so far indicate that these lipid chaperone proteins are proximal to the generation of inflammatory responses, especially upon exposure to lipids, and couple lipotoxicity to organelle function. More recently, we discovered that aP2 is secreted from adipocytes in response to lipolytic stimulation and during fasting, and acts on the liver to stimulate glucose production. Circulating aP2 levels are elevated in obese mice and humans, and high levels of circulating aP2 are strong and independent risk factors for metabolic disease. Remarkably, we demonstrated that aP2 neutralization with an antibody improved glucose tolerance and insulin sensitivity in obese mice. This strengthens our hypothesis that aP2 is a promising target for the development of new diabetes therapeutics.

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Crystal structure of the synthetic A-FABP inhibitor BMS309403 bound to human A-FABP

Biologically active lipids and nutrients:

In our studies on this theme we utilize a variety of technological platforms including chemical and genetic screens to explore functionally active fatty acids and other individual lipids and nutrients which have both critical intracellular functions and provide hormonal signals between adipose tissue and other metabolic organs such as liver and muscle tissues. Recently, using lipidomics, bioinformatics, and novel physiological systems, we identified an endogenous nutrient, C16:1n7-palmitoleate, as a lipokine, a fatty acid-based molecule with hormonal function. This lipokine is produced by fat and signals to the liver to modify hepatic lipogenesis and also to muscle to stimulate glucose disposal. Our studies further demonstrated that de novo lipogenesis in adipose tissue is a critical component of metabolic flexibility and homeostasis. Currently, we are exploring the mechanisms of action of this lipokine, searching for additional active fatty acid species and studying their metabolic effects and signaling mechanisms, and exploring the significance of adipose tissue de novo lipogenesis in systemic metabolism. In addition, we hope to generate additional strategies to to leverage these discovery efforts to create novel preventive and therapeutic opportunities against numerous chronic diseases including obesity, diabetes and atherosclerosis.

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Suggested reading from our lab:

Cao H, Sekiya M, Ertunc ME, Burak MF, Mayers JR, White A, Inouye K, Rickey LM, Ercal BC, Furuhashi M, Tuncman G, Hotamisligil GS. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metabolism 2013, 17(5):768-78. Abstract |PDF

Mozaffarian D, Cao H, King IB, Lemaitre RN, Song X, Siscovick DS, Hotamisligil GS. Trans-Palmitoleic Acid, Metabolic Risk Factors, and New-Onset Diabetes in US Adults. Ann Intern Med 2010, 21;153:790-9. Abstract | PDF

Erbay E, Babaev VR, Mayers JR, Makowski L, Charles KN, Snitow M, Fazio S, Wiest MM, Watkins SM, Linton MF, Hotamisligil GS. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nature Medicine, 2009, 12:1383-91. Abstract | PDF

Hotamisligil GS, Erbay E. Nutrient sensing and inflammation in metabolic diseases. Nature Reviews Immunology, 2008. Dec;8(12):923-34. Abstract | PDF

Cao H, Gerhold K, Mayers J, Wiest MW, Watkins SM, Hotamisligil GS. Identification of a lipokine, alipid hormone linking adipose tissue to systemic metabolism. Cell 2008, 134: 933-944. Abstract | PDF

Furuhashi M, Fucho R, Gorgun, Tuncman G, Cao H, Hotamisligil GS. Adipocyte/macrophage fattyacid-binding proteins contribute to metabolic deterioration through actions inboth macrophages and adipocytes in mice. The J of Clinical Investigation 2008, 118(7): 2640-50. Abstract | PDF

Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nature Reviews Drug Discovery 2008, 7(6): 489-503. Abstract | PDF

Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA,Parker RA, Hotamisligil GS. Treatment of diabetes and atherosclerosis byinhibiting fatty-acid-binding-protein aP2. Nature2007, 447(7147):959-65. Abstract | PDF

Makowski L, Brittingham KC, Reynolds JM, Suttles J, Hotamisligil GS. The fatty acid binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. J Biol Chem 2005, 280(13):12888-95. Abstract | PDF

Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, Uysal KT, Cao Q,Atsumi G, Malone H, Krishnan B, Minokoshi Y, Kahn BB, Parker RA,Hotamisligil, GS. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metabolism 2005, 1:107-119. Abstract | PDF

Makowski L and Hotamisligil GS. Fatty Acid Binding Proteins—The Evolutionary Crossroads of Inflammatory and Metabolic Responses. J of Nutrition, 2004, 134(9):2464S-2468S. Abstract | PDF

Boord JB, Maeda K, Makowski L, Babaev VR, Fazio S, Linton MF, Hotamisligil GS. Combined fatty acid-binding protein deficiency improves metabolism, reduces atherosclerosis, and increases survival in apolipoprotein E-deficient mice.Circulation 2004, 110(11):1492-1498. Abstract | PDF

Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF, Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nature Medicine 7(6):699-705, 2001. Abstract | PDF