GW501516对PPARβ/δ的激动作用增加肌管PGC-1α含量,降低BCAA培养基含量,而不依赖于BCAA分解代谢酶表达的变化。

IF 3.5 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL PPAR Research Pub Date : 2023-01-01 DOI:10.1155/2023/4779199
Caroline N Rivera, Jason S Hinkle, Rachel M Watne, Trent C Macgowan, Andrew J Wommack, Roger A Vaughan
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引用次数: 0

摘要

背景:2型糖尿病的特点是胰岛素敏感性降低,血液代谢产物升高,线粒体代谢减少,代谢调控基因表达减少,如过氧化物酶体增殖物激活受体γ辅助激活因子1- α (PGC-1α)。PGC-1α调节支链氨基酸(BCAA)代谢的表达,因此PGC-1α表达降低可能是糖尿病患者循环BCAA增加的部分原因。PGC-1α通过与过氧化物酶体增殖物激活受体β/δ (PPARβ/δ)相互作用发挥部分功能。本报告研究了PPARβ/δ激动作用对培养肌管细胞代谢和相关基因/蛋白表达的影响,重点研究了GW对BCAA处理和分解代谢酶表达的影响。方法:用GW501516 (GW)处理C2C12肌管达24小时。分别通过耗氧量和细胞外酸化率测定线粒体和糖酵解代谢。分别采用实时荧光定量聚合酶链反应(qRT-PCR)和western blot检测代谢基因和蛋白的表达。采用液相色谱-质谱法(LC/MS)测定培养基BCAA含量。结果:GW显著提高PGC-1α蛋白表达、线粒体含量和线粒体功能。24小时处理后,GW也显著降低了培养基中BCAA的含量;然而,BCAA分解代谢酶/转运蛋白的表达没有变化。结论:这些数据证实了GW能够增加肌肉PGC-1α含量,降低BCAA培养基含量,而不影响BCAA分解代谢酶/转运蛋白。这些发现表明,在相关细胞机制的蛋白质水平没有实质性变化的情况下,BCAA摄取(可能还有代谢)可能会增加。
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PPARβ/δ Agonism with GW501516 Increases Myotube PGC-1α Content and Reduces BCAA Media Content Independent of Changes in BCAA Catabolic Enzyme Expression.

Background: Type 2 diabetes is characterized by reduced insulin sensitivity, elevated blood metabolites, and reduced mitochondrial metabolism with reduced expression of genes governing metabolism such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). PGC-1α regulates the expression of branched-chain amino acid (BCAA) metabolism, and thus, increased circulating BCAA in diabetics may be partially explained by reduced PGC-1α expression. PGC-1α functions in-part through interactions with peroxisome proliferator-activated receptor β/δ (PPARβ/δ). The present report examined the effects of the PPARβ/δ agonism on cell metabolism and related gene/protein expression of cultured myotubes, with a primary emphasis on determining the effects of GW on BCAA disposal and catabolic enzyme expression.

Methods: C2C12 myotubes were treated with GW501516 (GW) for up to 24 hours. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Metabolic gene and protein expression were assessed via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Media BCAA content was assessed via liquid chromatography-mass spectrometry (LC/MS).

Results: GW significantly increased PGC-1α protein expression, mitochondrial content, and mitochondrial function. GW also significantly reduced BCAA content within culture media following 24-hour treatment; however, expression of BCAA catabolic enzymes/transporter was unchanged.

Conclusion: These data confirm the ability of GW to increase muscle PGC-1α content and decrease BCAA media content without affecting BCAA catabolic enzymes/transporter. These findings suggest heightened BCAA uptake (and possibly metabolism) may occur without substantial changes in the protein levels of related cell machinery.

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来源期刊
PPAR Research
PPAR Research MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.20
自引率
3.40%
发文量
17
审稿时长
12 months
期刊介绍: PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research focusing on mechanisms involved in the activation of peroxisome proliferator-activated receptors (PPARs), as well as their role in the regulation of cellular differentiation, development, energy homeostasis and metabolic function. The journal also welcomes preclinical and clinical trials of drugs that can modulate PPAR activity, with a view to treating chronic diseases and disorders such as dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, and obesity.
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