Toxicological Sciences
Toxicological Sciences
4 years ago

Sortilin 1 loss-of-function protects against cholestatic liver injury by attenuating hepatic bile acid accumulation in bile duct ligated mice.

Jaeschke H, Wang Y, Matye D, Woolbright BL, Li T, Li J, Hagenbuch B, Zhao W
Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid metabolism. This study further investigated the role of Sort1 in modulating bile acid detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 KO mice had attenuated liver injury 24 h after BDL, which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger bile acid pool size than sham-operated WT mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic bile acid accumulation and smaller bile acid pool size. After 14 days BDL, Sort1 KO mice showed significantly lower hepatic bile acid concentration and reduced expression of inflammatory and fibrotic marker genes, but similar degree of liver fibrosis compared to WT mice. Unbiased quantitative proteomics revealed that Sort1 KO mice had increased hepatic bile acid sulfotransferase 2A1, but unaltered phase-I bile acid metabolizing cytochrome P450s or phase-III bile acid efflux transporters. Consistently, Sort1 KO mice showed elevated plasma sulfated taurocholate after BDL. Finally, we found that liver Sort1 was repressed after BDL, which may be due to bile acid activation of farnesoid x receptor. In conclusion, we report a role of Sort1 in the regulation of hepatic bile acid detoxification and cholestatic liver injury in mice. The mechanisms underlying increased hepatic bile acid elimination in Sort1 KO mice after BDL require further investigation.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28453831

DOI: PubMed:28453831

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