Ashmore Tom, Roberts Lee D, Morash Andrea J, Kotwica Aleksandra O, Finnerty John, West James A, Murfitt Steven A, Fernandez Bernadette O, Branco Cristina, Cowburn Andrew S, Clarke Kieran, Johnson Randall S, Feelisch Martin, Griffin Julian L, Murray Andrew J
Department of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
Department of Biochemistry, University of Cambridge, Cambridge, UK.
BMC Biol. 2015 Dec 22;13:110. doi: 10.1186/s12915-015-0221-6.
Insulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of β-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms.
Herein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPARβ/δ- and PPARα-dependent mechanism. Enhanced PPARβ/δ and PPARα expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPARα(-/-) mice. In C2C12 myotubes, nitrate increased expression of the PPARα targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate supplementation.
Nitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.
骨骼肌中的胰岛素敏感性与代谢灵活性相关，包括在脂质供应增加时具有较高的增加脂肪酸（FA）氧化的能力。然而，脂质过载可导致FA氧化不完全以及潜在有害中间体的积累，此时线粒体三羧酸循环能力无法跟上β-氧化速率。因此，增强肌肉FA氧化并结合线粒体生物发生正成为一种治疗代谢疾病的策略。最近研究表明，膳食无机硝酸盐可通过尚未完全明确的机制逆转啮齿动物代谢综合征的某些方面。
在此，我们报告硝酸盐以剂量依赖的方式增强啮齿动物骨骼肌中的FA氧化。我们表明，硝酸盐通过可溶性鸟苷酸环化酶（sGC）/环磷酸鸟苷（cGMP）介导的PPARβ/δ和PPARα依赖性机制诱导FA氧化。增强的PPARβ/δ和PPARα表达及DNA结合诱导FA氧化酶的表达，增加肌肉肉碱并降低组织丙二酰辅酶A浓度，从而支持FA氧化的线粒体内途径并增强线粒体呼吸。在较高剂量下，硝酸盐诱导线粒体生物发生，进一步增加FA氧化并降低长链FA浓度。同时，硝酸盐对PPARα基因敲除小鼠的线粒体FA氧化没有影响。在C2C12肌管中，硝酸盐增加了PPARα靶标Cpt1b、Acadl、Hadh和Ucp3的表达，并用棕榈酰肉碱增强了氧化磷酸化速率；然而，sGC或蛋白激酶G的抑制可阻止基因表达和呼吸的这些变化。通过西地那非抑制磷酸二酯酶5使cGMP升高，也增加了Cpt1b、Acadl和Ucp3的表达以及CPT1B蛋白水平，并进一步增强了补充硝酸盐的效果。
因此，硝酸盐可能通过诱导肌肉中的FA氧化而有效治疗代谢疾病。
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