Bile acid regulation of xenobiotic nuclear receptors on the expressions of orosomucoids in the liver

Authors: SUH, JI HO - University Of Texas Health Science Center; CHEON, INYOUNG - University Of Texas Health Science Center; JUNG, HYUN-JUNG - University Of Texas Health Science Center; LEE, SUNG HO - Gwangju University; HEO, MI JEONG - University Of Texas Health Science Center; DEBERGE, MATTHEW - University Of Texas Health Science Center; WOOTEN-KEE, CLAVIA - Children'S Nutrition Research Center (CNRC); KIM, KANG HO - University Of Texas Health Science Center

Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/25/2025
Publication Date: 5/6/2025
Citation: Suh, J., Cheon, I., Jung, H., Lee, S., Heo, M., DeBerge, M., Wooten-Kee, C.R., Kim, K. 2025. Bile acid regulation of xenobiotic nuclear receptors on the expressions of orosomucoids in the liver. American Journal of Physiology. 328:E940-E951. https://doi.org/10.1152/ajpendo.00417.2024.
DOI: https://doi.org/10.1152/ajpendo.00417.2024

Interpretive Summary: The liver is the major organ for handling metabolism and clearance of toxins, and we found that bile acids (a derivative of cholesterol that is essential for absorption of fat-soluble nutrients) increase the expression of endocrine-like compounds called orosomucoids (Orm1 and Orm2). Specifically, bile acids are ligands for transcription factors in the liver that leads to an increase in Orm1 and Orm2. Orm1 and Orm2 serve as signals to the fat tissue to improve glucose homeostasis.

Technical Abstract: Wilson disease (WD) is an autosomal recessive disorder that results in excessive hepatic copper, causing hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver failure. Previous studies have revealed dysregulation of many farnesoid X receptor (FXR) metabolic target genes in WD, including the bile salt exporter pump, the major determinant of bile flow. We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis. FXR binding within Atp7b-/- mouse livers displayed surprising complexity: FXR binding was increased in distal intergenic regions but decreased in promoter regions in Atp7b-/- versus wild-type mice. Decreased FXR occupancy in Atp7b-/- versus wild-type mice was observed in hepatocyte metabolic and bile acid homeostasis pathways, while enrichment of FXR binding was observed in pathways associated with cellular damage outside of hepatocytes. Indeed, disparate FXR occupancy was identified in parenchymal and non-parenchymal marker genes in a manner that suggests decreased FXR activity in parenchymal cells, as expected, and increased FXR activity in non-parenchymal cells. Consistent with altered FXR function, serum and liver bile acid concentrations were higher in Atp7b-/- mice than in wild-type mice. Comparison of bile acid profiles in the serum of WD patients with “liver,” “neurological,” or “mixed” disease versus healthy controls also revealed increases in specific bile acids in WD-liver versus healthy controls. We identified novel FXR-occupancy across the genome that varied in parenchymal and non-parenchymal cells, demonstrating complex FXR regulation of metabolic and hepatocellular stress pathways in Atp7b-/- mice. Dynamic changes in FXR activity support our novel finding of altered bile acid metabolism in Atp7b-/- mice and WD patients.