LPL调控脂联素高聚化的分子机制

Adiponectin is an important insulin-sensitizing adipokine with multiple beneficial effects on obesity-associated medical complications. It is secreted from adipocytes into the circulation as trimer (LMW), hexamer (MMW) and the high-molecular-weight (HMW) of 18-36 monomers, with the HMW oligomer possessing the most potent insulin-sensitizing activity. The composition of adiponectin oligomers in circulation, particularly the ratio of HMW to total adiponectin, varies under different obesity-related pathological conditions, and can be reversed by pharmacological and lifestyle interventions. Therefore, adiponectin is a promising candidate for the development of drugs to treat type 2 diabetes and other related metabolic diseases. LPL (lipoprotein lipase) is an enzyme that hydrolyzes triglycerides in lipoproteins, such as chylomicrons and very low-density lipoproteins. LPL was identified as one of the proteins which can be immunoprecipitated by antibodies specific for adiponectin oligomers in our research. We found that LPL interacts with adiponectin and promotes adiponectin multimerization. In this study, we will investigate the molecular mechanism by with LPL promotes adiponectin multimerization. This study reveals a novel function of LPL, which will help to identify potential drug targets for the treatment of type 2 diabetes.

脂联素是由脂肪组织特异性分泌的具有胰岛素增敏作用的激素，在血清内以低聚体、中聚体和高聚体的形式存在，其中高聚体是脂联素调控代谢作用的主要活性形式。通过提高脂联素高聚体在血清中所占的比例，可以有效地改善2型糖尿病患者的胰岛素敏感性，同时也为开发和研制治疗2型糖尿病的药物开辟了新的研究领域。 我们的前期研究证明，激活AMPK信号通路能够促进脂联素高聚体的形成。LPL(Lipoprotein Lipase)是脂蛋白代谢中重要的脂蛋白酯肪酶，主要催化乳糜微粒和极低密度脂蛋白中甘油三酯的分解。本实验室前期实验发现，LPL可以与脂联素多聚体结合，并且促进脂联素的高聚化。在本项目中，我们将进一步验证LPL与脂联素之间的相互结合，探究LPL调控脂联素高聚化的分子机制。本课题将揭示LPL的新功能，为深入研究脂联素高聚化的调控机制，寻找机体内治疗2型糖尿病新型药物靶点奠定理论基础。

脂联素是一种由脂肪细胞大量表达并分泌的细胞因子，在机体中发挥着调节能量代谢、改善胰岛素抵抗、抗炎、抗氧等多种生理功能。脂联素在血清中主要以三种形式存在：低聚体、中聚体和高聚体，不同聚体发挥着不同的生理功能。研究表明脂联素高聚体是调节糖脂代谢的主要活性形式，而其高聚体的形成机制却尚不明确。因此，研究脂联素的高聚化能够为相关疾病的治疗与药物开发提供新思路。.在本项目中，我们发现LP不仅与脂联素相互结合，而且能够促进脂联素的高聚化。我们证明LPL调控脂联素的高聚化与LPL的脂酶活性无关，与LPL的正常分泌密切相关。 LPL不是通过被AMPK磷酸化调控脂联素高聚体的组装；而是作为AMPK的上游调控蛋白，通过与脂联素和脂联素受体AdipoR1在细胞膜上结合，激活AMPK信号通路，从而促进脂联素高聚体的组装。我们的发现对于深入了解脂联素高聚化的调控机制十分重要，也为寻找治疗二型糖尿病等代谢类疾病药物奠定了理论基础。..