Osteocytes/Osteoblasts Produce SAA3 to Regulate Hepatic Metabolism of Cholesterol

Abstract 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 Dmp1 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 Dmp1 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.