Lipid Chaperones, Trafficking, Signaling and Metabolic Regulation

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 the major emphasis on diabetes is focused on dysregulation of glucose metabolism, there are equally important alterations in lipid metabolism. Despite their critical role in metabolichomeostasis and disease, it has been challenging to determine the mechanisms of lipid actions and their specific involvement with critical regulatory or toxic pathways.

 

 

We approach the molecular basis of these interactions by focusing on the biological role of lipid chaperones in intra-cellular lipid trafficking and signaling as well as inter-organ communications. These small proteins bind to lipids and dictate their composition, partitioning, and function in cells. The two isoforms present in adipocytes and macrophages have a profound impact on metabolism. We have developed several mouse models that are deficient in adipocyte/macrophage FABPs (fatty acid binding proteins also known as aP2 and mal1, or FABP4 and FABP5) and demonstrated that these animals were 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 andFABP-deficient mice exhibit resistance to allergic airway inflammation, raising the possibility of a molecular link between metabolism and airway function. Our mechanistic studies so far indicate that these lipid chaperone proteins are proximal to generation of the inflammatory responses, especially upon exposure to lipids, and couple lipotoxicity to organelle function. Currently, we are trying to establish the components of the signaling pathway that is controlled by lipid chaperones, their specific functions in adipocytes and macrophages,and the mechanisms by which these pathways are linked to inflammatory and metabolic responses.

In our studies on this theme we utilize a variety of technological platforms including chemical and genetic screens to explore functionally activefatty acids and other individual lipids which are critical in bothintracellular functions and provide hormonal signals between adipose tissue andother metabolic organs such as liver and muscle tissues. Recently, using lipidomics and bioinformaticstools and novel physiological systems, we identified C16:1n7-palmetoleate as afatty acid-based hormone or “lipokine”. Itis produced by fat and signals the liver to modify hepatic lipogenesis and signalsmuscle to stimulate glucose disposal. Our studies also demonstrated that de novo lipogenesis in adiposetissue is a critical component of metabolic homeostasis. Currently, we are exploring the mechanisms of action of this lipokine, searching for additional activefatty acid species and studing their metabolic effects and signalingmechanisms. In addition, we hope togenerate chemical strategies to regulate lipid chaperones and their targets tocreate novel preventive and therapeutic opportunities against numerous chronicdiseases including obesity, diabetes and atherosclerosis.

Suggested reading from Hotamisligil Lab:

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

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, 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

Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, AtsumiG, 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

Furuhashi M, Fucho R, Gorgun, Tuncman G, Cao H, HotamisligilGS. 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

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

Furuhashi M, Hotamisligil GS. Regulation of metabolic homeostasis through a family of fatty acid-binding proteins. Nature Reviews Drug Discovery 2008, 7(6): 489-503. Abstract | PDF