The Lipin Protein Family and Triglyceride Metabolism

脂蛋白（lipin-1、lipin-2和lipin-3）对三酰甘油（TAG）代谢至关重要，这是三酰甘油代谢的一个关键主题。 我们的计划项目。脂蛋白具有磷脂酸磷酸酶（PAP）酶活性并催化 TAG合成中的倒数第二步，将磷脂酸转化为二酰基甘油。脂蛋白还与 与转录调节因子一起调节基因表达。Lipin-1表达水平和活性影响 肥胖、胰岛素抵抗、肝脏和肌肉脂质稳态、能量消耗和外周神经 髓鞘形成lipin-2和lipin-3的生理作用还没有得到很好的表征。人脂蛋白-2 缺乏会导致Majeed综合征，其特征是骨骼炎症和贫血。的 这种疾病的机制尚不清楚，这突出了更好地了解生理学的必要性。 和脂蛋白的病理生理学。事实上，人们对lipin-3的生理作用一无所知。 我们的建议是基于我们对lipin-2的生物学作用的三个发现 和Iipin-3。首先是脂蛋白-2基因敲除的小鼠有异常 在骨生长板中，脂蛋白-2定位于生长板中的细胞-软骨细胞。在 目的1明确lipin-2在软骨细胞分化中的作用及其机制 与脂蛋白-2缺乏相关的潜在骨异常。这些发现可能会提供新的见解 马吉德综合征骨骼异常的发病机制第二个发现是脂肪组织 PAP活性和TAG积累不仅由lipin-1决定，也由lipin-3决定。我们绘制了 lipin-1和lipin-3之间的物理相互作用，表明两者都需要的机制基础 脂肪组织中的脂蛋白。我们的研究结果关于lipin-3-的作用和lipin-1和 脂蛋白-3-在脂肪细胞的功能可能是相关的人类脂肪组织生物学，因为平衡 lipin-1和lipin-3之间的差异可能影响lipin-1缺陷小鼠和人类的差异易感性 明显的脂肪代谢障碍第三个发现是lipin-2和lipin-3各自对小细胞中的PAP活性有贡献。 这两种蛋白质的损失导致细胞溶质TAG液滴在肠中的急剧积累。 肠细胞我们认为lipin-2和lipin-3 PAP活性对肠道脂质稳态是重要的 和乳糜微粒组装。考虑到肠道TAG在这一过程中的作用， 合成主要归因于单酰基甘油途径。我们的研究将为一个 小肠脂质代谢的基本过程。 .

The lipin proteins (lipin-1, lipin-2, and lipin-3) are critical for triacylglycerol (TAG) metabolism, a key theme of our Program Project. Lipin proteins have phosphatidate phosphatase (PAP) enzyme activity and catalyze the penultimate step in TAG synthesis, converting phosphatidic acid to diacylglycerol. Lipins also interact with transcriptional regulators to modulate gene expression. Lipin-1 expression levels and activity influence adiposity, insulin resistance, liver and muscle lipid homeostasis, energy expenditure, and peripheral nerve myelination. The physiological roles of lipin-2 and lipin-3 are much less well characterized. Human lipin-2 deficiency causes Majeed Syndrome, which is distinguished by bone inflammation and anemia. The mechanism for this disease is unknown and highlights the need for a better understanding ofthe physiology and pathophysiology of lipin proteins. Virtually nothing is known about the physiological role of lipin-3. Our proposal is based on three discoveries that we have made regarding the biological roles of lipin-2 and iipin-3 using our lipin-deficient mouse models. The first is that lipin-2 knockout mice have abnormalities in the bone growth plate, and lipin-2 is localized to cells that populate the growth plate—the chondrocytes. In Aim 1 we will define the role of lipin-2 in chondrocyte differentiation and determine the mechanisms underlying bone abnormalities associated with lipin-2 deficiency. The findings may provide fresh insights into the pathogenesis of bone abnormalities in Majeed syndrome. A second discovery is that adipose tissue PAP activity and TAG accumulation are determined not only by lipin-1, but also by lipin-3. We have mapped a physical interaction between lipin-1 and lipin-3, suggesting a mechanistic basis forthe requirement of both lipins in adipose tissue. Our findings regarding the role of lipin-3—and the interaction between lipin-1 and lipin-3—in adipocyte function are likely to be relevant to human adipose tissue biology, since the balance between lipin-1 and lipin-3 may influence the differential susceptibility of lipin-1-deficient mice and humans to overt lipodystrophy. A third discovery is that lipin-2 and lipin-3 each contribute to PAP activity in the small intestine, and that the loss of both proteins leads to a dramatic accumulation of cytosolic TAG droplets in enterocytes. We propose that lipin-2 and lipin-3 PAP activities are important for intestinal lipid homeostasis and chylomicron assembly. The implication of lipins in this process is novel given that intestinal TAG synthesis has been attributed primarily to the monoacylglycerol pathway. Our studies will shed new light on a fundamental process of lipid metabolism in the small intestine. .