title: Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2.
abstract: Chronic inflammation in obese adipose tissue is linked to endoplasmic reticulum (ER) stress and systemic insulin resistance. Targeted deletion of the murine fatty acid binding protein (FABP4/aP2) uncouples obesity from inflammation although the mechanism underlying this finding has remained enigmatic. Here, we show that inhibition or deletion of FABP4/aP2 in macrophages results in increased intracellular free fatty acids (FFAs) and elevated expression of uncoupling protein 2 (UCP2) without concomitant increases in UCP1 or UCP3. Silencing of UCP2 mRNA in FABP4/aP2-deficient macrophages negated the protective effect of FABP loss and increased ER stress in response to palmitate or lipopolysaccharide (LPS). Pharmacologic inhibition of FABP4/aP2 with the FABP inhibitor HTS01037 also upregulated UCP2 and reduced expression of BiP, CHOP, and XBP-1s. Expression of native FABP4/aP2 (but not the non-fatty acid binding mutant R126Q) into FABP4/aP2 null cells reduced UCP2 expression, suggesting that the FABP-FFA equilibrium controls UCP2 expression. FABP4/aP2-deficient macrophages are resistant to LPS-induced mitochondrial dysfunction and exhibit decreased mitochondrial protein carbonylation and UCP2-dependent reduction in intracellular reactive oxygen species. These data demonstrate that FABP4/aP2 directly regulates intracellular FFA levels and indirectly controls macrophage inflammation and ER stress by regulating the expression of UCP2.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Ann V
authors.initials: AV
authors.lastname: Hertzel
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kaylee A
authors.initials: KA
authors.lastname: Steen
authors.affiliation: College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA bernl001@umn.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Bernlohr
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics*; D008070:Lipopolysaccharides / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D007473:Ion Channels; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2