Metabolic alterations of the gut-liver axis induced by cholic acid contribute to hepatic steatosis in rats

12 alpha-Hydroxylated (12 alpha OH) bile acids (BAs) selectively increase with high-fat diet intake. Dietary supplemen-tation with cholic acid (CA) in rats is a possible strategy to reveal the causal link between 12 alpha OH BAs and hepatic steatosis. The present study aimed to investigate the metabolic mechanism underlying the effect of 12 alpha OH BAs on hepatic steatosis. Male WKAH rats were fed either a control (Ct) or CA-supplemented diet (0.5 g/kg). After the 12-week intervention, the CA diet elevated the 12 alpha OH BA levels in the gut-liver axis. CA-fed rats showed greater hepatic lipid accumulation than in the Ct group, regardless of the dietary energy balance. Untargeted metab-olomics suggested marked differences in the fecal metabolome of rats subjected to the CA diet compared with that of Ct, characterized by the depletion of fatty acids and enrichment of amino acids and amines. Moreover, the liver metabolome differed in the CA group, characterized by an alteration in redox-related pathways. The CA diet elevated nicotinamide adenine dinucleotide consumption owing to the activation of poly(ADP-ribose) poly-merase 1, resulting in impaired peroxisome proliferator-activated receptor alpha signaling in the liver. The CA diet increased sedoheptulose 7-phosphate, and enhanced glucose-6-phosphate dehydrogenase activity, suggesting promotion of the pentose phosphate pathway that generates reducing equivalents. Integrated analysis of the gut-liver metabolomic data revealed the role of deoxycholic acid and its liver counterpart in mediating these metabolic alterations. These observations suggest that alterations in metabolites induced by 12 alpha OH BAs in the gut-liver axis contribute to the enhancement of liver lipid accumulation.

Automated summary

High-fat diet intake can selectively increase the levels of 12 alpha-Hydroxylated bile acids (BAs). Supplementing rats with cholic acid (CA) is a possible strategy to investigate the causal link between 12 alpha OH BAs and hepatic steatosis. The metabolic mechanism underlying the effect of 12 alpha OH BAs on hepatic steatosis was investigated using untargeted metabolomics. The study found that alterations in metabolites induced by 12 alpha OH BAs in the gut-liver axis contribute to the enhancement of liver lipid accumulation.