State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Adv Sci (Weinh). 2024 Jun;11(24):e2307818. doi: 10.1002/advs.202307818. Epub 2024 Apr 13.
Hypercholesterolaemia is a systemic metabolic disease, but the role of organs other than liver in cholesterol metabolism is unappreciated. The phenotypic characterization of the Tsc1 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 Tsc1 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.
高胆固醇血症是一种全身性代谢疾病，但肝脏以外的器官在胆固醇代谢中的作用尚未被充分认识。Tsc1 基因敲除小鼠的表型特征表明，成骨细胞/成骨细胞（Dmp1-Cre）中结节性硬化复合物 1（TSC1）的基因缺失会触发血清胆固醇水平的逐渐升高。研究结果表明，胆固醇代谢失调与骨和血清中分别上调和升高与脂质代谢相关的因子血清淀粉样蛋白 A3（SAA3）有关。骨中产生的 SAA3 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）的表达来阻止胆固醇转化为胆汁酸。在 Tsc1 小鼠中敲除 Saa3 可防止肝脏中 CYP7A1 减少和血清中胆固醇升高。这些结果扩展了对骨骼功能和肝脏调节胆固醇代谢的理解，并揭示了药物调节 SAA3 在高胆固醇血症中的潜在治疗用途。
