Multi-omics analysis reveals osteocyte loss as a potential trigger for liver lipid metabolic disorder

Bone regulates whole-body homeostasis via secretory proteins, and clinical observations have suggested potential links between certain skeletal pathologies and liver abnormalities under specific clinical contexts.

This study established a postnatal-specific osteocyte knockout mouse model (Dmp1^cre DTR^fl/fl). Livers were collected for Single-cell RNA sequencing (scRNA-seq), bulk transcriptomic analysis, and metabolomic analysis to reveal the impact of osteocytes ablation on liver metabolism. Multi-omics analysis revealed alterations in lipid metabolism, with upregulation of Cyp4a10 related to oxidative stress and lipid peroxidation, and downregulation of Scd1 involved in fatty acid biosynthesis. scRNA-seq identified changes in gene expression patterns in hepatocytes, endothelial cells, and Kupffer cells, with key transcription factors (Yy1 in hepatocytes and Etv5 in endothelial cells) associated with steatosis. Altered cellular communication networks, particularly the Grn-sort1 and Angptl4-Sdc axes, potentially reshaped liver metabolism and facilitated steatosis in Dmp1^cre DTR^fl/fl mice. Histological analysis confirmed the development of hepatic steatosis in Dmp1^cre DTR^fl/fl mice.

Loss of osteocytes has potential role in liver lipid metabolic disturbances and fat accumulation, mediated through the modulation of lipid and inflammatory gene expression and alterations in intra-cellular communication within the liver. These findings enhance our understanding of how bone disease can initiate systemic metabolic disorders and provide support for the concept of the bone-liver axis.