title: Regulation of AMPK activation by CD36 links fatty acid uptake to β-oxidation.
abstract: Increases in muscle energy needs activate AMPK and induce sarcolemmal recruitment of the fatty acid (FA) translocase CD36. The resulting rises in FA uptake and FA oxidation are tightly correlated, suggesting coordinated regulation. We explored the possibility that membrane CD36 signaling might influence AMPK activation. We show, using several cell types, including myocytes, that CD36 expression suppresses AMPK, keeping it quiescent, while it mediates AMPK activation by FA. These dual effects reflect the presence of CD36 in a protein complex with the AMPK kinase LKB1 (liver kinase B1) and the src kinase Fyn. This complex promotes Fyn phosphorylation of LKB1 and its nuclear sequestration, hindering LKB1 activation of AMPK. FA interaction with CD36 dissociates Fyn from the protein complex, allowing LKB1 to remain cytosolic and activate AMPK. Consistent with this, CD36(-/-) mice have constitutively active muscle and heart AMPK and enhanced FA oxidation of endogenous triglyceride stores. The molecular mechanism described, whereby CD36 suppresses AMPK, with FA binding to CD36 releasing this suppression, couples AMPK activation to FA availability and would be important for the maintenance of cellular FA homeostasis. Its dysfunction might contribute to the reported association of CD36 variants with metabolic complications of obesity in humans.
authors.affiliation: Department of Medicine, Center for Human Nutrition, Washington University School of Medicine in St. Louis, St. Louis, MO Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, MO dsamovsk@dom.wustl.edu nabumrad@dom.wustl.edu.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Samovski
authors.affiliation: Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, MO.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Medicine, Center for Human Nutrition, Washington University School of Medicine in St. Louis, St. Louis, MO.
authors.forename: Terri
authors.initials: T
authors.lastname: Pietka
authors.affiliation: Department of Medicine, Center for Human Nutrition, Washington University School of Medicine in St. Louis, St. Louis, MO Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes, University of Colorado, Denver, CO.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Soochow University, Suzhou, People's Republic of China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, MO.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stahl
authors.affiliation: Department of Medicine, Center for Human Nutrition, Washington University School of Medicine in St. Louis, St. Louis, MO Department of Cell Biology & Physiology, Washington University School of Medicine in St. Louis, St. Louis, MO dsamovsk@dom.wustl.edu nabumrad@dom.wustl.edu.
authors.forename: Nada A
authors.initials: NA
authors.lastname: Abumrad
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D008077:Lipoproteins, LDL; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D010084:Oxidation-Reduction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051076:Proto-Oncogene Proteins c-fyn; D014280:Triglycerides
chemical_list: D018955:CD36 Antigens; D005227:Fatty Acids; D008077:Lipoproteins, LDL; D014280:Triglycerides; C099252:oxidized low density lipoprotein; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases