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Principal Investigator: Mikhail G Kolonin
Organization: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
Fiscal Year: 2019
Award: $368,900
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
White adipose tissue (WAT) is the main lipid reservoir that becomes dysfunctional in obesity. It is important to understand how breached lipid homeostasis leads to metabolic disease. Efficient long chain fatty acid (FA) and cholesterol trafficking depends on a transmembrane transporter protein CD36. However, the mechanism through which CD36 switches from uptake to mobilization of lipids and how lipids traffic between the endothelium and adipocytes is not understood. We had previously identified a WAT-specific plasmalemmal interaction between prohibitin-1 (PHB) and annexin A2 (ANX2). To study its role on the surface of endothelial cells (EC) and adipocytes, we have been supported by grant R01DK088131 from the NIDDK. We have shown that PHB/ANX2 binding in the context of lipid rafts mediates FA transport from EC to adipocytes, hence promoting adipocyte lipid deposition. As we recently reported, PHB and ANX2 interact with CD36 on the cell membrane within a complex assembled in response to extracellular FA. Our preliminary data suggest that FA also trigger interaction of PHB and CD36 on the surface of tumor cells, in which function of these proteins has been independently linked to cancer aggressiveness. In this competing renewal application, we propose to investigate the assembly of the PHB/ANX2/CD36 complex and its role in lipid import and export in WAT endothelium, adipocytes, and cancer cells. Our underlying hypothesis is that a spike in either extracellular or intracellular FA brings together PHB, ANX2 and CD36, which then cooperate in either FA uptake or FA mobilization, respectively. By using mice and cell culture models in which PHB or CD36 are deleted in endothelial cells or adipocytes, we will test if these proteins are necessary for lipid import into adipocytes (Specific Aim 1) and for lipolysis-induced lipid mobilization from WAT (Specific Aim 2). Our collaborator, Dr. Maria Febbraio, has generated a mouse model for tissue-specific CD36 deletion, and preliminary data demonstrate CD36 importance in EC for FA and cholesterol homeostasis. We will also use the inter-cellular lipid transport assay that we have designed to study lipid exchange between EC and adipocytes and the function of PHB/ANX2/CD36 interaction in lipogenic and lipolytic conditions. By using cell culture systems in which the protein interaction is disrupted either genetically or pharmacologically, we will also test the function of the PHB/ANX2/CD36 complex in lipid transport from WAT to malignant cells and in cancer chemoresistance and progression (Specific Aim 3). Finally, based on the reported requirement of CD36 palmitoylation for its localization to lipid rafts and for activation of lipid transport, we hypothesize that S-acylation is the trigger of the PHB/ANX2/CD36 complex assembly. Specifically, based on our preliminary data, we hypothesize that CD36 S-acylation occurs upon extracellular or intracellular FA concentration increase. We will collaborate with Dr. Askar Akimzhanov, an expert in protein S-acylation, to test if this process enables FA-induced assembly of the PHB/ANX2/CD36 complex to serve as a switch for context-dependent lipid uptake or mobilization.
Terms: <ACRP30 protein><Acylation><Adipocytes><Adipose Cell><Adipose Tissue Neoplasms><Adipose Tissue Tumor><Adipose tissue><Adult-Onset Diabetes Mellitus><Annexins><Assay><Autoregulation><BAP32 protein><Binding><Binding Proteins><Bioassay><Biologic Assays><Biological Assay><Blood Vessels><CD36><CD36 Antigens><CD36 Fatty Acid Transporter><CD36 gene><CD36 protein><Calcimedins><Cancer Model><CancerModel><Cancers><Carcinoma Cell><Carrier Proteins><Cell Body><Cell Communication and Signaling><Cell Culture System><Cell Culture Techniques><Cell Membrane Lipid Rafts><Cell Signaling><Cell membrane><Cells><Cholesterol><Cholesterol Homeostasis><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cofactor Protein S><Collaborations><Complex><Cytoplasmic Membrane><Data><Defect><Deposit><Deposition><Diet><Drug resistance><Dysfunction><Endothelial Cells><Endothelium><Fat Cells><Fatty Acids><Fatty Tissue><Functional disorder><GP3B><GP4><GPIV><GPIV Platelet Glycoprotein><Genetic><Grant><Health><Homeostasis><Homing><Human><Hypertrophy><Immune Precipitation><Immunoprecipitation><Impairment><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Knowledge><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Lipid Mobilization><Lipid Trafficking><Lipids><Lipocortins><Lipocytes><Lipolysis><Lipomatous Tumor><Lipomatous neoplasm><Malignant Cell><Malignant Epithelial Cell><Malignant Neoplasms><Malignant Tumor><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Membrane Microdomains><Metabolic><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><NIDDK><NIDDM><National Institute of Diabetes and Digestive and Kidney Diseases><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><Obesity><Peptides><Pharmacology><Phb1 protein><Phb2 protein><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Plasma Membrane><Play><Process><Protein Binding><Protein S><Proteins><Reporting><Role><SCARB3><SR-BI receptor><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Stable Diabetes Mellitus><Stimulus><Surface><T2 DM><T2D><T2DM><Testing><Thesaurismosis><Thrombospondin Receptors><Tissue Model><Transport Protein Gene><Transport Proteins><Transporter Protein><Tumor Cell><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vitamin K-Dependent Protein S><Work><adipocyte complement-related protein 30-kDa><adipocyte, C1q and collagen domain containing protein><adiponectin><adipose><adiposity><adult onset diabetes><apM-1 protein><apM1 (adipose-specific) protein><base><biological signal transduction><bound protein><cancer cell><cancer progression><cancer survival><cell culture><cell type><cholesterol metabolism><cholesterol trafficking><corpulence><corpulency><corpulentia><design><designing><dietary><drug resistant><extracellular><fatty acid transport><fatty acylation><interventional strategy><ketosis resistant diabetes><lipid raft><lipid transport><long chain fatty acid><malignancy><maturity onset diabetes><metabolism disorder><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><obese><obese people><obese person><obese population><palmitoylation><pathophysiology><plasmalemma><prohibitin><promoter><promotor><protein complex><protein function><recruit><resistance to Drug><resistant to Drug><response><scavenger receptor B type I><scavenger receptor B1><scavenger receptor BI><scavenger receptor class B type I><scavenger receptors, class B, type I><social role><tumor><tumor progression><type 2 DM><type II DM><type two diabetes><uptake><vascular><white adipose tissue><yellow adipose tissue>