Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism.
Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism.
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DOI：
10.1186/s12915-015-0221-6
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发表时间：
2015-12-22
期刊：
影响因子：
5.4
通讯作者：
Murray AJ
中科院分区：
文献类型：
--
作者：
Ashmore T;Roberts LD;Morash AJ;Kotwica AO;Finnerty J;West JA;Murfitt SA;Fernandez BO;Branco C;Cowburn AS;Clarke K;Johnson RS;Feelisch M;Griffin JL;Murray AJ
骨骼肌中的胰岛素敏感性与代谢灵活性相关，包括响应于增加的脂质供应而增加脂肪酸（FA）氧化的高能力。然而，脂质超负荷可导致FA氧化不完全和潜在有害中间体的蓄积，其中线粒体三羧酸循环能力无法跟上β-氧化速率。因此，结合线粒体生物合成增强肌肉FA氧化正在成为治疗代谢性疾病的策略。膳食无机硝酸盐最近被证明可以逆转啮齿动物代谢综合征的各个方面，其机制尚未完全确定。在此，我们报告说，硝酸盐增强骨骼肌脂肪酸氧化在啮齿动物中的剂量依赖性的方式。我们发现硝酸盐通过可溶性鸟苷酸环化酶（sGC）/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表达和DNA结合诱导FA氧化酶的表达，增加肌肉肉毒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合成，进一步增加FA氧化并降低长链FA浓度。同时，硝酸盐并不影响PPARα−/−小鼠的线粒体FA氧化。在C2 C12肌管中，硝酸盐增加了PPARα靶点Cpt 1b、Acadl、Hadh和Ucp 3的表达，并增强了棕榈酰肉碱的氧化磷酸化速率;然而，这些基因表达和呼吸的变化可通过抑制sGC或蛋白激酶G来阻止。通过西地那非抑制磷酸二酯酶5，cGMP的升高也增加了Cpt 1b，Acadl和Ucp 3的表达，以及CPT 1B蛋白水平，并进一步增强了硝酸盐补充的效果。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性疾病。本文的在线版本（doi：10.1186/s12915-015-0221-6）包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1186/s12915-015-0221-6) contains supplementary material, which is available to authorized users.