Leukotriene-B4 modulates macrophage metabolism and fat loss in type 1 diabetic mice.
Adiposity
/ drug effects
Animals
Biomarkers
/ metabolism
Diabetes Mellitus, Type 1
/ metabolism
Down-Regulation
/ drug effects
Energy Metabolism
/ drug effects
Fatty Acids
/ metabolism
Glycolysis
/ drug effects
Hyperlipidemias
/ metabolism
Leukotriene B4
/ pharmacology
Lipogenesis
/ drug effects
Liver
/ drug effects
Macrophages, Peritoneal
/ drug effects
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Oxidation-Reduction
/ drug effects
Signal Transduction
/ drug effects
Uncoupling Protein 1
/ metabolism
energetic metabolism
hyperlipidemia
leukotriene-B4
macrophage
type 1 diabetes
uncoupling cellular respiration
Journal
Journal of leukocyte biology
ISSN: 1938-3673
Titre abrégé: J Leukoc Biol
Pays: England
ID NLM: 8405628
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
31
12
2018
revised:
31
05
2019
accepted:
10
06
2019
pubmed:
27
6
2019
medline:
27
5
2020
entrez:
27
6
2019
Statut:
ppublish
Résumé
Serum levels of leukotriene-B4 (LTB4) are increased in type 1 diabetes (T1D) and it mediates systemic inflammation and macrophage reprogramming associated with this condition. Herein, we investigated the involvement of LTB4 in adiposity loss, hyperlipidemia, and changes in macrophage metabolism in a mouse model of streptozotocin-induced T1D. LTB4 receptor (BLT1) antagonist u75302 was employed to block LTB4 effects. As expected, hypoinsulinemia in T1D was associated with hyperglycemia, low levels of glucagon, hyperlipidemia, significant body fat loss, and increased white adipose tissue expression of Fgf21, a marker for lipolysis. With the exception of hyperglycemia and hypoglucagonemia, blockade of LTB4 signaling reverted these parameters in T1D mice. Along with hyperlipidemia, macrophages from T1D mice exhibited higher lipid uptake and accumulation. These cells also had enhanced glycolysis and oxidative metabolism and these parameters were dependent on the mitochondrial uncoupling respiration, as evidenced by elevated expression of oxidation markers carnitine palmitoyltransferase and uncoupling protein 1. Interestingly, all these parameters were at least partially reverted in T1D mice treated with u75302. Altogether, these findings suggest that in T1D mice LTB4/BLT1 is involved in the fat loss, hyperlipidemia, and increased macrophage lipid uptake and metabolism with an important involvement of mitochondrial uncoupling activity. These previously unrecognized LTB4/BLT1 functions may be explored in future to therapeutically alleviate severity of hyperlipidemia and systemic inflammation in T1D.
Identifiants
pubmed: 31242337
doi: 10.1002/JLB.MA1218-477RR
doi:
Substances chimiques
Biomarkers
0
Fatty Acids
0
Uncoupling Protein 1
0
Leukotriene B4
1HGW4DR56D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
665-675Informations de copyright
©2019 Society for Leukocyte Biology.
Références
Hebert SL, Nair KS. Protein and energy metabolism in type 1 diabetes. Clin Nutr. 2010;29:13-17.
Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40-50.
Rosenfalck AM, Almdal T, Hilsted J, Madsbad S. Body composition in adults with Type 1 diabetes at onset and during the first year of insulin therapy. Diabet Med. 2002;19:417-423.
Hink U, Tsilimingas N, Wendt M, Münzel T. Mechanisms underlying endothelial dysfunction in diabetes mellitus: therapeutic implications. Treat Endocrinol. 2003;2:293-304.
Kono H, Onda A, Yanagida T. Molecular determinants of sterile inflammation. Curr Opin Immunol. 2014;26:147-156.
Ramalho T, Filgueiras L, Silva-Jr I, Pessoa AFM, Jancar S. Impaired wound healing in type 1 diabetes is dependent on 5-lipoxygenase products. Scientific Reports (Nature). 2018.
Filgueiras LR, Brandt SL, Wang S, et al. Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes. Sci Signal. 2015;8:ra10.
Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014;6:13.
Castoldi A, Naffah de Souza C, Câmara NO, Moraes-Vieira PM. The macrophage switch in obesity development. Front Immunol. 2015;6:637.
Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292-2333.
Willecke F, Scerbo D, Nagareddy P, et al. Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice. Arterioscler Thromb Vasc Biol. 2015;35:102-110.
Rial E, Rodríguez-Sánchez L, Gallardo-Vara E, Zaragoza P, Moyano E, González-Barroso MM. Lipotoxicity, fatty acid uncoupling and mitochondrial carrier function. Biochim Biophys Acta. 2010;1797:800-806.
Choi SH, Harkewicz R, Lee JH, et al. Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake. Circ Res. 2009;104:1355-1363.
Tessaro FH, Ayala TS, Martins JO. Lipid mediators are critical in resolving inflammation: a review of the emerging roles of eicosanoids in diabetes mellitus. Biomed Res Int. 2015;2015:568408.
Serezani CH, Lewis C, Jancar S, Peters-Golden M. Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression. J Clin Invest. 2011;121:671-682.
Spite M, Hellmann J, Tang Y, et al. Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. J Immunol. 2011;187:1942-1949.
Li P, Oh DY, Bandyopadhyay G, et al. LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes. Nat Med. 2015;21:239-247.
Peters-Golden M, Henderson WR. Leukotrienes. N Engl J Med. 2007;357:1841-1854.
Ramalho T, Filgueiras L, Marçal-Pessoa AF, Jancar S. Impaired wound healing in type 1 diabetes is dependent on 5-lipoxygenase products. Scientific Reports (Nature). 2018.
Pighin D, Karabatas L, Pastorale C, et al. Role of lipids in the early developmental stages of experimental immune diabetes induced by multiple low-dose streptozotocin. J Appl Physiol (1985). 2005;98:1064-1069.
O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553-565.
Tan Z, Xie N, Cui H, et al. Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol. 2015;194:6082-6089.
Cannon B, Shabalina IG, Kramarova TV, Petrovic N, Nedergaard J. Uncoupling proteins: a role in protection against reactive oxygen species-or not?. Biochim Biophys Acta. 2006;1757:449-458.
de Haan JB, Cooper ME. Targeted antioxidant therapies in hyperglycemia-mediated endothelial dysfunction. Front Biosci (Schol Ed). 2011;3:709-729.
Whitman SA, Long M, Wondrak GT, Zheng H, Zhang DD. Nrf2 modulates contractile and metabolic properties of skeletal muscle in streptozotocin-induced diabetic atrophy. Exp Cell Res. 2013;319:2673-2683.
Iv Jones, R A, , Coleman EL, et al. Type 1 diabetes alters lipid handling and metabolism in human fibroblasts and peripheral blood mononuclear cells. PLoS One. 2017;12:e0188474.
Hotta Y, Nakamura H, Konishi M, et al. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology. 2009;150:4625-4633.
Das SK, Eder S, Schauer S, et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science. 2011;333:233-238.
Pepino MY, Kuda O, Samovski D, Abumrad NA. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu Rev Nutr. 2014;34:281-303.
Pourcet B, Staels B. Alternative macrophages in atherosclerosis: not always protective!. J Clin Invest. 2018;128:910-912.
Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante AW. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab. 2013;18:816-830.
Gundra UM, Girgis NM, Ruckerl D, et al. Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct. Blood. 2014;123:e110-22.
Divakaruni AS, Hsieh WY, Minarrieta L, et al. Etomoxir inhibits macrophage polarization by disrupting CoA homeostasis. Cell Metab. 2018.
Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell. 2012;151:400-413.
Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol. 2007;178:3912-3917.
Torkildsen G, Lonsdale J, Geffin J, Gjorstrup P. 2009. https://clinicaltrials.gov/ct2/show/NCT00799552. Volume 2019, U.S. National Library of Medicine. Accessed February 26, 2019.
Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018;128:2657-2669.