Fig 8. Proposed downstream site of calcium protection from liver injury.

In the current study, calcium supplementation did not affect weight gain or hepatic steatosis, but did decrease the incidence of NASH-related histological changes, including fibrosis and regenerative hyperplasia associated with “end-stage” NASH. Thus, calcium supplementation could prevent the adverse downstream effects of obesity in situations where weight loss cannot be achieved or maintained. Although the mechanism is not known, potential factors could include gut chelation of bile acids or altered bile acid pools that may be related to gut microbial shifts. Calcium supplementation in this study was associated with decreased hepatic tauro-β- muricholic acid, which reduces FXR antagonism in the liver, permitting FXR-mediated inhibition of total bile acid synthesis. The decrease in hepatic total bile acid synthesis may decrease available substrate for downstream intestinal bacterial conversion of primary bile acids to cytotoxic secondary bile acids (LCA, DCA). Since a percentage of these bile acids are re-absorbed in the colon and transported to liver, the decrease in their synthesis could limit hepatic exposure to potentially cytotoxic BA molecular species.