Nardi Francesca, Lipina Christopher, Magill David, Hage Hassan Rima, Hajduch Eric, Gray Alexander, Hundal Harinder S
Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, UMR-S 872, Paris, France; Université Pierre et Marie Curie - Paris 6, UMR-S 872, Paris, France; Université Paris Descartes, UMR-S 872, Paris, France.
PLoS One. 2014 Mar 14;9(3):e92255. doi: 10.1371/journal.pone.0092255. eCollection 2014.
AIMS/HYPOTHESIS: Reduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation.
We treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt- and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine307phosphorylation - events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.
CONCLUSIONS/INTERPRETATION: Beneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A.
目的/假设：骨骼肌胰岛素敏感性降低是持续暴露于过量饱和脂肪酸（SFA）所伴随的一个特征，而单不饱和脂肪酸和多不饱和脂肪酸（MUFA和PUFA）不仅能改善胰岛素敏感性，还能减轻SFA诱导的胰岛素抵抗。MUFA和PUFA产生这些有利变化的机制尚不清楚，但可能涉及通过对蛋白磷酸酶2A（PP2A）的反调节/抑制来刺激胰岛素信号传导。本研究调查了油酸（OA；一种MUFA）、亚油酸（LOA；一种PUFA）和棕榈酸（PA；一种SFA）对培养的肌管的影响，并确定胰岛素信号的变化是否可归因于PP2A的调节。
我们用不饱和脂肪酸和饱和脂肪酸处理培养的骨骼肌肌管，并评估胰岛素信号传导、PP2A催化亚基的磷酸化和甲基化状态。与PA不同，用OA或LOA持续孵育大鼠或人肌管可显著增强Akt和ERK1/2介导的胰岛素信号传导。这不是由于上游IRS1或PI3K信号增强，也不是由于近端胰岛素信号传导相关蛋白的表达变化，而是与Akt和ERK1/2的去磷酸化/失活减少有关。与此一致，PA降低了PP2Ac的去甲基化和酪氨酸307磷酸化，这些事件与PP2A激活有关。相比之下，OA和LOA强烈对抗PA诱导的PP2Ac的这些变化，从而对PP2A发挥抑制作用。
结论/解读：胰岛素敏感性的有益提高以及不饱和脂肪酸在肌肉细胞中对抗棕榈酸诱导的胰岛素抵抗的能力，可能部分归因于PP2A的反调节。
