PPAR-α agonism improves whole body and muscle mitochondrial fat oxidation, but does not alter intracellular fat concentrations in burn trauma children in a randomized controlled trial
Tóm tắt
Insulin resistance is often associated with increased levels of intracellular triglycerides, diacylglycerol and decreased fat β-oxidation. It was unknown if this relationship was present in patients with acute insulin resistance induced by trauma. A double blind placebo controlled trial was conducted in 18 children with severe burn injury. Metabolic studies to assess whole body palmitate oxidation and insulin sensitivity, muscle biopsies for mitochondrial palmitate oxidation, diacylglycerol, fatty acyl Co-A and fatty acyl carnitine concentrations, and magnetic resonance spectroscopy for muscle and liver triglycerides were compared before and after two weeks of placebo or PPAR-α agonist treatment. Insulin sensitivity and basal whole body palmitate oxidation as measured with an isotope tracer increased significantly (P = 0.003 and P = 0.004, respectively) after PPAR-α agonist treatment compared to placebo. Mitochondrial palmitate oxidation rates in muscle samples increased significantly after PPAR-α treatment (P = 0.002). However, the concentrations of muscle triglyceride, diacylglycerol, fatty acyl CoA, fatty acyl carnitine, and liver triglycerides did not change with either treatment. PKC-θ activation during hyper-insulinemia decreased significantly following PPAR-α treatment. PPAR-α agonist treatment increases palmitate oxidation and decreases PKC activity along with reduced insulin sensitivity in acute trauma, However, a direct link between these responses cannot be attributed to alterations in intracellular lipid concentrations.
Tài liệu tham khảo
Wolfe RR: Glucose metabolism in burn injury: a review. J Burn Care Rehabil 1985,6(5):408-418. 10.1097/00004630-198509000-00005
Wolfe RR, Herndon DN, Jahoor F, Miyoshi H, Wolfe M: Effect of severe burn injury on substrate cycling by glucose and fatty acids. N Engl J Med 1987,317(7):403-408.
Padfield KE, Astrakas LG, Zhang Q, Gopalan S, Dai G, Mindrinos MN, Tompkins RG, Rahme LG, Tzika AA: Burn injury causes mitochondrial dysfunction in skeletal muscle. Proc Natl Acad Sci U S A 2005,102(15):5368-5373. 10.1073/pnas.0501211102
He J, Watkins S, Kelley DE: Skeletal muscle lipid content and oxidative enzyme activity in relation to muscle fiber type in type 2 diabetes and obesity. Diabetes 2001,50(4):817-823. 10.2337/diabetes.50.4.817
Kelley DE, Simoneau JA: Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. J Clin Invest 1994,94(6):2349-2356.
Shulman GI: Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology (Bethesda) 2004, 19: 183-190.
Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC, Berge RK, Staels B: Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 2000,275(22):16638-16642. 10.1074/jbc.275.22.16638
Chou CJ, Haluzik M, Gregory C, Dietz KR, Vinson C, Gavrilova O, Reitman ML: WY14,643, a peroxisome proliferator-activated receptor alpha (PPARalpha ) agonist, improves hepatic and muscle steatosis and reverses insulin resistance in lipoatrophic A-ZIP/F-1 mice. J Biol Chem 2002,277(27):24484-24489. 10.1074/jbc.M202449200
Young ME, Goodwin GW, Ying J, Guthrie P, Wilson CR, Laws FA, Taegtmeyer H: Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids. Am J Physiol Endocrinol Metab 2001,280(3):E471-9.
Furuhashi M, Ura N, Murakami H, Hyakukoku M, Yamaguchi K, Higashiura K, Shimamoto K: Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle. J Endocrinol 2002,174(2):321-329. 10.1677/joe.0.1740321
Muoio DM, Way JM, Tanner CJ, Winegar DA, Kliewer SA, Houmard JA, Kraus WE, Dohm GL: Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells. Diabetes 2002,51(4):901-909. 10.2337/diabetes.51.4.901
Tan CE, Chew LS, Tai ES, Chio LF, Lim HS, Loh LM, Shepherd J: Benefits of micronised Fenofibrate in type 2 diabetes mellitus subjects with good glycemic control. Atherosclerosis 2001,154(2):469-474. 10.1016/S0021-9150(00)00497-4
Damci T, Tatliagac S, Osar Z, Ilkova H: Fenofibrate treatment is associated with better glycemic control and lower serum leptin and insulin levels in type 2 diabetic patients with hypertriglyceridemia. Eur J Intern Med 2003,14(6):357-360. 10.1016/S0953-6205(03)90001-X
Forcheron F, Cachefo A, Thevenon S, Pinteur C, Beylot M: Mechanisms of the triglyceride- and cholesterol-lowering effect of fenofibrate in hyperlipidemic type 2 diabetic patients. Diabetes 2002,51(12):3486-3491. 10.2337/diabetes.51.12.3486
Cree MG, Qian T, Herndon DN, Morio B, Fram RY, Zwetsloot JJ, Sanford AP, Aarsland A, Wolfe RR: Fenofibrate improves insulin sensitivity and mitochondrial function in children with burn injury. Ann Surg 2007,245(2):214-21. 10.1097/01.sla.0000250409.51289.ca
Cree MG, Newcomer BR, Katsanos CS, Sheffield-Moore M, Chinkes D, Aarsland A, Urban R, Wolfe RR: Intramuscular and liver triglycerides are increased in the elderly. J Clin Endocrinol Metab 2004,89(8):3864-3871. 10.1210/jc.2003-031986
Pereira C, Murphy K, Jeschke M, Herndon DN: Post burn muscle wasting and the effects of treatments. Int J Biochem Cell Biol 2005,37(10):1948-1961. 10.1016/j.biocel.2005.05.009
Wolfe RR: Radioactive and Stable Isotope Tracers in Biomedicine. New York , Wiley-Liss; 1992.
Wolfe R, Chinkes D: Isotope Tracers in Metabolic Research. 2nd edition. Wiley-Liss; 2005.
Thyfault JP, Cree MG, Zheng D, Zwetsloot JJ, Tapscott EB, Koves TR, Ilkayeva O, Wolfe RR, Muoio DM, Dohm GL: Contraction of insulin resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism. Am J Physiol Cell Physiol 2006.
Sun D, Cree MG, Zhang XJ, Boersheim E, Wolfe RR: Measurement of stable isotopic enrichment and concentration of long-chain fatty acyl-carnitines in tissue by HPLC-MS. J Lipid Res 2006,47(2):431-439. 10.1194/jlr.D500026-JLR200
Sun D, Cree MG, Wolfe RR: Quantification of the concentration and (13)C tracer enrichment of long-chain fatty acyl-coenzyme A in muscle by liquid chromatography/mass spectrometry. Anal Biochem 2006,349(1):87-95. 10.1016/j.ab.2005.10.006
Morio B, Hocquette JF, Montaurier C, Boirie Y, Bouteloup-Demange C, McCormack C, Fellmann N, Beaufrere B, Ritz P: Muscle fatty acid oxidative capacity is a determinant of whole body fat oxidation in elderly people. Am J Physiol Endocrinol Metab 2001,280(1):E143-9.
Veksler VI, Kuznetsov AV, Sharov VG, Kapelko VI, Saks VA: Mitochondrial respiratory parameters in cardiac tissue: a novel method of assessment by using saponin-skinned fibers. Biochim Biophys Acta 1987,892(2):191-196. 10.1016/0005-2728(87)90174-5
Alp PR, Newsholme EA, Zammit VA: Activities of citrate synthase and NAD+-linked and NADP+-linked isocitrate dehydrogenase in muscle from vertebrates and invertebrates. Biochem J 1976,154(3):689-700.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 1951,193(1):265-275.
Zhou Q, Dolan PL, Dohm GL: Dephosphorylation increases insulin-stimulated receptor kinase activity in skeletal muscle of obese Zucker rats. Mol Cell Biochem 1999,194(1-2):209-216. 10.1023/A:1006942831223
Fram RY, Cree MG, Herndon DN, Chinkes DL, Lee JO, Sanford AP, Barrow RE, Wolfe RR: The recovery of labelled acetate in severly burned children 7 days after injury. Faseb J 2006,20(4):A169.
Murakami K, Tobe K, Ide T, Mochizuki T, Ohashi M, Akanuma Y, Yazaki Y, Kadowaki T: A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes 1998,47(12):1841-1847. 10.2337/diabetes.47.12.1841
Minnich A, Tian N, Byan L, Bilder G: A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle. Am J Physiol Endocrinol Metab 2001,280(2):E270-9.
Martini WZ, Irtun O, Chinkes DL, Rasmussen B, Traber DL, Wolfe RR: Alteration of hepatic fatty acid metabolism after burn injury in pigs. JPEN J Parenter Enteral Nutr 2001,25(6):310-316.
Ferre P: The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 2004, 53 Suppl 1: S43-50. 10.2337/diabetes.53.2007.S43
Petersen KF, Shulman GI: Etiology of insulin resistance. Am J Med 2006,119(5 Suppl 1):S10-6. 10.1016/j.amjmed.2006.01.009
An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI, Koves TR, Stevens R, Millington D, Newgard CB: Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 2004,10(3):268-274. 10.1038/nm995
Ye JM, Iglesias MA, Watson DG, Ellis B, Wood L, Jensen PB, Sorensen RV, Larsen PJ, Cooney GJ, Wassermann K, Kraegen EW: PPARalpha /gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly. Am J Physiol Endocrinol Metab 2003,284(3):E531-40.
Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EW: Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes 2001,50(2):411-417. 10.2337/diabetes.50.2.411
Ide T, Tsunoda M, Mochizuki T, Murakami K: Enhancement of insulin signaling through inhibition of tissue lipid accumulation by activation of peroxisome proliferator-activated receptor (PPAR) alpha in obese mice. Med Sci Monit 2004,10(10):BR388-95.
Schmitz-Peiffer C: Protein kinase C and lipid-induced insulin resistance in skeletal muscle. Ann N Y Acad Sci 2002, 967: 146-157.
Laybutt DR, Schmitz-Peiffer C, Saha AK, Ruderman NB, Biden TJ, Kraegen EW: Muscle lipid accumulation and protein kinase C activation in the insulin-resistant chronically glucose-infused rat. Am J Physiol 1999,277(6 Pt 1):E1070-6.
Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ: Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 1997,46(2):169-178. 10.2337/diabetes.46.2.169
Itani SI, Pories WJ, Macdonald KG, Dohm GL: Increased protein kinase C theta in skeletal muscle of diabetic patients. Metabolism 2001,50(5):553-557. 10.1053/meta.2001.22512