Laboratory of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 71003, Greece.
Laboratory of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion 71003, Greece,.
Biochim Biophys Acta Gene Regul Mech. 2017 Aug;1860(8):848-860. doi: 10.1016/j.bbagrm.2017.05.007. Epub 2017 May 31.
Lipoprotein lipase (LPL) catalyzes the hydrolysis of triglycerides from triglyceride-rich lipoproteins such as VLDL and chylomicrons in the circulation. Mutations in LPL or its activator apolipoprotein C-II cause hypertriglyceridemia in humans and animal models. The levels of LPL in the liver are low but they can be strongly induced by a high cholesterol diet or by synthetic ligands of Liver X Receptors (LXRs). However, the mechanism by which LXRs activate the human LPL gene is unknown. In the present study we show that LXR agonists increased the mRNA and protein levels as well as the promoter activity of human LPL in HepG2 cells. A promoter deletion analysis defined the proximal -109/-28 region, which contains a functional FOXA2 element, as essential for transactivation by ligand-activated LXRα/RXRα heterodimers. Silencing of endogenous FOXA2 in HepG2 cells by siRNAs or by treatment with insulin compromised the induction of the LPL gene by LXR agonists whereas mutations in the FOXA2 site abolished the synergistic transactivation of the LPL promoter by LXRα/RXRα and FOXA2. Physical and functional interactions between LXRα and FOXA2 were established in vitro and ex vivo. In summary, the present study revealed a novel mechanism of human LPL gene induction by oxysterols in the liver with is based on physical and functional interactions between transcription factors LXRα and FOXA2. This mechanism, which may not be restricted to the LPL gene, is critically important for a better understanding of the regulation of cholesterol and triglyceride metabolism in the liver under healthy or pathological states.
脂蛋白脂肪酶（LPL）催化循环中富含甘油三酯的脂蛋白，如 VLDL 和乳糜微粒中的甘油三酯水解。LPL 或其激活物载脂蛋白 C-II 的突变会导致人类和动物模型中的高甘油三酯血症。肝脏中的 LPL 水平较低，但它们可以被高胆固醇饮食或肝 X 受体（LXRs）的合成配体强烈诱导。然而，LXR 激活人 LPL 基因的机制尚不清楚。在本研究中，我们表明 LXR 激动剂增加了 HepG2 细胞中人 LPL 的 mRNA 和蛋白水平以及启动子活性。启动子缺失分析定义了近端 -109/-28 区域，该区域包含一个功能性 FOXA2 元件，对于配体激活的 LXRα/RXRα 异二聚体的转录激活是必需的。HepG2 细胞中内源性 FOXA2 的 siRNA 沉默或胰岛素处理削弱了 LXR 激动剂对 LPL 基因的诱导作用，而 FOXA2 位点的突变则消除了 LXRα/RXRα 和 FOXA2 对 LPL 启动子的协同转录激活作用。LXRα 和 FOXA2 之间的体外和体内物理和功能相互作用得到了确立。总之，本研究揭示了肝脏中氧化固醇诱导人 LPL 基因表达的新机制，该机制基于转录因子 LXRα 和 FOXA2 之间的物理和功能相互作用。这种机制可能不仅限于 LPL 基因，对于更好地理解健康或病理状态下肝脏中胆固醇和甘油三酯代谢的调节至关重要。
