Bile acids and nonalcoholic fatty liver disease: An intriguing relationship

Non-alcoholic fatty liver disease (NAFLD) stands nowadays as a leading cause of progressive impairment of liver function. The role of bile acids in the modulation of hepatic lipid metabolism is interesting and controversial; previous evidence showed an inhibitory effect of bile acids on lipogenesis, which was attributed to the activation of the FXR-SHP axis and consequent depression of the LXRα-SREBP-1c lipogenic pathway. Evidence from our research group has shown that both exogenous administration of bile acids and endogenous exposure to bile acid overload (as in cholestasis) may reduce hepatic fat accumulation in rat models, although by different mechanisms. The findings in the paper by Nagahashi et al are quite surprising, showing the development of fatty liver disease in SphK2 -/- mice, in association with a decreased expression of SREBP1c and lipogenic enzymes like FAS. The metabolic effects of bile acids on hepatic lipid metabolism seem to be strictly dependent on the experimental model utilized to induce fat liver accumulation, as well as on the modality of bile acid exposure (exogenous vs endogenous) and the relative activation of the LXR/FXR pathways. Experimental evidence like that brought by Nagahashi et al1 may bring an enormous contribution in this field, in the perspective of novel pharmacological targets for the treatment of NAFLD.