Bile acids and nonalcoholic fatty liver disease: An intriguing relationship

Potential conflict of interest: Nothing to report. To the Editor: Nonalcoholic fatty liver disease stands nowadays as a leading cause of progressive impairment of liver function. We read with great interest the paper by Nagahashi et al.1 recently published in Hepatology which highlights the role of conjugated bile acids, sphingosine‐1 phosphate receptor 2, and sphingosine kinase 2 in regulating hepatic lipid metabolism and liver lipid content. Such results are exciting and stimulating. The role of bile acids in the modulation of hepatic lipid metabolism is interesting and controversial; previous evidence by Watanabe et al.2 showed an inhibitory effect of bile acids on lipogenesis, which was attributed to activation of the farnesoid X receptor (FXR)–small heterodimer partner (SHP) axis and consequent depression of the liver X receptor (LXR)‐α–sterol regulatory element binding protein (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 mechanisms3: (1) by activating of the FXR‐SHP axis and (2) by inducing cytochrome P450 7A1, which leads to reduced oxysterol hepatic bioavailability and in turn down‐regulation of the LXR‐α–controlled lipogenic pathway. The findings in the paper by Nagahashi et al.1 are quite surprising, showing the development of fatty liver disease in SphK2–/– mice in association with decreased expression of SREBP 1c and lipogenic enzymes like FAS. As the authors comment, hepatic fat accumulation might be induced by mechanisms different from increased lipogenesis, such as the reduction of lipid and lipoprotein output from the liver, according to previous evidence in humans.4 Data from our group are consistent with this hypothesis. Indeed, we detected a beneficial effect of cholic acid feeding in the choline‐deficient dietary model (in which hepatic lipid export is reduced) but not in the high‐fat model.2 In other words, 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 versus endogenous) and the relative activation of the LXR and FXR pathways. Experimental evidence like that brought by Nagahashi et al.1 may bring an enormous contribution to this field, in the perspective of novel pharmacological targets for the treatment of nonalcoholic fatty liver disease.