A combination of dietary cholesterol and cholic acid induces hepatic expression of proinflammatory genes accompanied by changes in sterol metabolism and redox status.

Oxidized sterols and redox status play an important role in the enhancement of lipid accumulation and exacerbation of symptoms in the liver. In this study, we examined whether the combination of dietary supplementation with cholesterol (Chol) and cholic acid (CA) modulates sterol metabolism and factors related to lipid accumulation in the liver. C57BL/6J male mice (4-week-old) were fed diets containing Chol at 3 g/kg and/or CA at 0.5 g/kg for 6 weeks. The lipid parameters, sterol metabolism, and hepatic gene expression were analyzed. An increase in hepatic triglyceride and fatty acid concentrations was observed in mice fed the Chol-supplemented diets. No additional effect of CA supplementation was observed on triglyceride concentration in the liver. Chol supplementation enhanced the fecal excretion of β-muricholic acid, whereas CA supplementation enhanced the circulation of enterohepatic 12-hydroxylated bile acids. Notably, the combination of dietary Chol and CA supplementation synergistically increased the concentrations of 4β-hydroxycholesterol and the gene expression of some inflammation-related factors in the liver. Similar changes were observed in the expression of ATP-binding cassette transporters (Abcg5 and Abcg8). The hepatic concentrations of some oxysterols, including 4β-hydroxycholesterol, were correlated with the expression of ATP-binding cassette transporters and glutathione S-transferases (Gsta1 and Gstm1). This suggests that the combination of dietary Chol and CA supplementation synergistically enhances Chol oxidation and proinflammatory events, accompanied by an alteration in the redox balance in the liver of mice, which may be an early symptom of liver disorders. SIGNIFICANCE STATEMENT: This study revealed that a combination of dietary cholesterol (Chol) and cholic acid (CA) supplementation synergistically increased oxysterol concentrations, muricholic acid excretion, and the expression of genes for inflammatory responses and Chol transport-related factors in the mouse liver. Chol increased the ratio of reduced glutathione/oxidized glutathione in the liver, whereas this ratio was modulated in combination with CA. This study highlights individual and synergistic roles of Chol and CA in Chol oxidation, bile acid metabolism, and inflammatory responses in the liver.