Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Int J Mol Sci. 2020 Nov 6;21(21):8338. doi: 10.3390/ijms21218338.
Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer's disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, , and have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.
脂蛋白脂肪酶（LPL）是脂质和脂蛋白代谢中的关键酶。LPL 的典型作用涉及水解富含甘油三酯的脂蛋白，为代谢组织提供游离脂肪酸。然而，LPL 也可能通过作为脂蛋白与细胞表面受体之间的分子桥，促进脂蛋白的摄取。最近的研究表明，LPL 在大脑中大量表达，主要在人类和鼠脑的巨噬细胞和小胶质细胞中表达。此外，最近的研究结果表明，LPL 在小胶质细胞功能、代谢和对细胞外因子如淀粉样蛋白-β（Aβ）的吞噬作用中发挥直接作用。尽管 LPL 在大脑中的确切功能仍有待确定，但已有几项研究表明 LPL 变异与阿尔茨海默病（AD）风险相关。例如，虽然已证明某些突变对 LPL 功能和表达具有有害影响（例如，N291S、和 与 AD 风险增加相关，但与桥接功能增加相关的突变（S447X）可能对 AD 具有保护作用。最近的研究还表明，内源性 LPL 激活剂（ApoC-II）和抑制剂（ApoC-III）的遗传变异可分别增加和降低 AD 风险，这与 LPL 可能在 AD 发病机制中发挥保护作用的观点一致。在这里，我们综述了对 LPL 结构和功能的最新认识，这些认识主要指向功能性 LPL 在 AD 神经病理学中的保护作用。
