肝脏内PP2A通过肝脏分泌LCAT调节“肝骨轴”改善肝性骨病的机制研究

肝脏作为人体重要代谢器官，通过“肝脑轴”和“肝肠轴”调控机体稳态，一旦稳态平衡被破坏，便会引发各类代谢疾病。目前肝脏与骨骼间稳态调节研究较少。我们从“肝骨轴”角度，以慢性肝损伤导致的代谢性骨骼疾病—肝性骨病为突破点，结合临床病例和实验动物模型研究发现：调控90%以上蛋白质去磷酸化修饰的磷酸酶PP2A的催化亚基cα在肝脏内的表达同肝性骨病显著相关；肝脏内特异性敲除PP2Acα能够通过促进肝脏特异性分泌代谢分子LCAT(卵磷脂胆固醇脂酰基转移酶)，远端调控成骨细胞和破骨细胞活性，改善肝性骨病。本课题将从临床、分子、细胞、组织水平，采用肝脏特异性敲除小鼠，系统研究肝脏内PP2A调控肝脏特异性分泌LCAT，调节骨代谢，影响肝性骨病的具体分子机制，阐明在生理和病理条件下肝脏与骨骼间远端调控，维持机体稳态的作用方式，结合靶向治疗的研究，为肝性骨病治疗提供理论基础和治疗靶点。

As an important metabolic organ of human body, the liver regulates the homeostasis through "liver brain axis" and "liver intestine axis". Once the axial balance is destroyed, it will cause various metabolic diseases. However, the axial regulation between the liver and the bones of non classical endocrine organs has not been established. From the perspective of "liver bone axis", we take the hepatic osteodystrophy disease（HOD） caused by chronic liver injury as a breakthrough point. Combined with clinical samples and experimental animal models, we preliminarily found that the expression of catalytic subunit C α of PP2A, which regulates the dephosphorylation of more than 90% of protein, is significantly related to HOD; the deficiency of PP2Ac α in liver can promote LCAT (lecithin cholesterol acyltransferase) secreted specifically by liver to regulate the activity of osteoblasts and osteoclasts and improve HOD. In this project, we will systematically study PP2A, as an important regulator of the "liver bone axis", on regulating bone metabolism and affecting the molecular mechanism of HOD by specifically secreting LCAT from the liver, as to explain that the information exchange between liver and bone modulates the homeostasis of the body under physiological and pathological conditions and providing targeted therapy for HOD.