Bile acids amplify the gender gap in hepatocellular carcinoma

Liver is a principal metabolic organ and one of the exclusive tasks of the liver is to synthesize bile acids. Bile acids, the body’s natural detergents are now well recognized as active signaling molecules. Physiological... [ view full abstract ]

Liver is a principal metabolic organ and one of the exclusive tasks of the liver is to synthesize bile acids. Bile acids, the body’s natural detergents are now well recognized as active signaling molecules. Physiological concentration of bile acids is maintained by a negative feedback loop coordinated by nuclear receptors Farnesoid X Receptor (Fxr) and Small Heterodimer Partner (Shp). Previously we showed that when these two nuclear receptors (DKO) are deleted pathological accumulation of bile acids occurs and leads to spontaneous liver carcinogenesis. Here we report that the development of hepatocellular carcinoma (HCC) in the DKO mice is gender-specific and selectively affects only the male mice. We find that the DKO female mice accumulate half the amount of serum bile acids indicating that female mice may control bile acid levels differently than the male mice. Based on this data we hypothesized that increasing bile acids levels should induce HCC in female DKO mice. Indeed DKO female mice fed with DDC diet exhibit elevated serum bile acid levels and also developed HCC. Next we examined whether (i) decreased bile acid synthesis or (ii) increased bile acid breakdown was responsible for the reduced bile acid levels in DKO female mice. While we found no difference in the bile acid synthesis, in the DKO female mice we discovered a dramatic induction of sulfo-transferases (Sults), which are responsible for sulfating and excretion of bile acid levels. Overall, our findings show that DKO female mice by excreting excess bile acids are protected against developing HCC.