首页> 美国卫生研究院文献>other >Phospholipase C-Related Catalytically Inactive Protein (PRIP) Regulates Lipolysis in Adipose Tissue by Modulating the Phosphorylation of Hormone-Sensitive Lipase
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Phospholipase C-Related Catalytically Inactive Protein (PRIP) Regulates Lipolysis in Adipose Tissue by Modulating the Phosphorylation of Hormone-Sensitive Lipase

机译:磷脂酶C相关的催化失活蛋白(PRIP)通过调节激素敏感性脂酶的磷酸化来调节脂肪组织中的脂解

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摘要

Phosphorylation of hormone-sensitive lipase (HSL) and perilipin by protein kinase A (PKA) promotes the hydrolysis of lipids in adipocytes. Although activation of lipolysis by PKA has been well studied, inactivation via protein phosphatases is poorly understood. Here, we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a binding partner for protein phosphatase 1 and protein phosphatase 2A (PP2A), is involved in lipolysis by regulating phosphatase activity. PRIP knockout (PRIP-KO) mice displayed reduced body-fat mass as compared with wild-type mice fed with standard chow ad libitum. Most other organs appeared normal, suggesting that mutant mice had aberrant fat metabolism in adipocytes. HSL in PRIP-KO adipose tissue was highly phosphorylated compared to that in wild-type mice. Starvation of wild-type mice or stimulation of adipose tissue explants with the catabolic hormone, adrenaline, translocated both PRIP and PP2A from the cytosol to lipid droplets, but the translocation of PP2A was significantly reduced in PRIP-KO adipocytes. Consistently, the phosphatase activity associated with lipid droplet fraction in PRIP-KO adipocytes was significantly reduced and was independent of adrenaline stimulation. Lipolysis activity, as assessed by measurement of non-esterified fatty acids and glycerol, was higher in PRIP-KO adipocytes. When wild-type adipocytes were treated with a phosphatase inhibitor, they showed a high lipolysis activity at the similar level to PRIP-KO adipocytes. Collectively, these results suggest that PRIP promotes the translocation of phosphatases to lipid droplets to trigger the dephosphorylation of HSL and perilipin A, thus reducing PKA-mediated lipolysis.
机译:蛋白激酶A(PKA)使激素敏感性脂肪酶(HSL)和周脂肪素磷酸化,可促进脂肪细胞中脂质的水解。尽管已经对通过PKA激活脂解作用进行了深入研究,但对通过蛋白质磷酸酶进行灭活的了解却很少。在这里,我们调查了磷脂酶C相关的催化失活蛋白(PRIP),蛋白磷酸酶1和蛋白磷酸酶2A(PP2A)的结合伴侣,是否通过调节磷酸酶活性参与脂质分解。与随意喂食标准松鼠的野生型小鼠相比,PRIP基因敲除(PRIP-KO)小鼠的体脂质量降低。大多数其他器官看起来正常,这表明突变小鼠的脂肪细胞中脂肪代谢异常。与野生型小鼠相比,PRIP-KO脂肪组织中的HSL被高度磷酸化。用分解代谢激素,肾上腺素刺激野生型小鼠饥饿或刺激脂肪组织外植体,将PRIP和PP2A都从胞质溶胶转移到脂质滴中,但PP2A在PRIP-KO脂肪细胞中的转移明显减少。一致地,与PRIP-KO脂肪细胞中脂质滴分数相关的磷酸酶活性显着降低,并且与肾上腺素刺激无关。通过测量非酯化脂肪酸和甘油评估的脂解活性在PRIP-KO脂肪细胞中更高。用磷酸酶抑制剂处理野生型脂肪细胞时,它们显示出与PRIP-KO脂肪细胞相似的高脂解活性。总体而言,这些结果表明PRIP促进磷酸酶向脂质小滴的转运,从而触发HSL和周脂蛋白A的去磷酸化,从而减少PKA介导的脂解。

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