Hypercholesterolaemia is a systemic metabolic disease, but the role of organs other than liver in cholesterol metabolism is unappreciated. The phenotypic characterization of the Tsc1Dmp1 mice reveal that genetic depletion of tuberous sclerosis complex 1 (TSC1) in osteocytes/osteoblasts (Dmp1‐Cre) triggers progressive increase in serum cholesterol level. The resulting cholesterol metabolic dysregulation is shown to be associated with upregulation and elevation of serum amyloid A3 (SAA3), a lipid metabolism related factor, in the bone and serum respectively. SAA3, elicited from the bone, bound to toll‐like receptor 4 (TLR4) on hepatocytes to phosphorylate c‐Jun, and caused impeded conversion of cholesterol to bile acids via suppression on cholesterol 7 α‐hydroxylase (Cyp7a1) expression. Ablation of Saa3 in Tsc1Dmp1 mice prevented the CYP7A1 reduction in liver and cholesterol elevation in serum. These results expand the understanding of bone function and hepatic regulation of cholesterol metabolism and uncover a potential therapeutic use of pharmacological modulation of SAA3 in hypercholesterolaemia.

中文翻译：

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骨细胞/成骨细胞产生 SAA3 调节肝脏胆固醇代谢

高胆固醇血症是一种全身代谢性疾病，但肝脏以外的器官在胆固醇代谢中的作用尚未得到重视。表型特征TSC1数据管理1小鼠揭示了骨细胞/成骨细胞中结节性硬化症复合体 1 (TSC1) 的基因缺失（数据管理1‐克里）引发血清胆固醇水平逐渐升高。由此产生的胆固醇代谢失调与骨骼和血清中血清淀粉样蛋白 A3 (SAA3) 的上调和升高有关，血清淀粉样蛋白 A3 是一种脂质代谢相关因子。 SAA3，从骨骼中提取，与肝细胞上的 Toll 样受体 4 (TLR4) 结合，磷酸化 c-Jun，并通过抑制胆固醇7α-羟化酶（CYP7a1） 表达。消融萨阿3在TSC1数据管理1小鼠阻止肝脏中 CYP7A1 的减少和血清中胆固醇的升高。这些结果扩展了对骨功能和肝脏对胆固醇代谢调节的理解，并揭示了 SAA3 药理学调节在高胆固醇血症中的潜在治疗用途。