Bile acids in nonalcoholic steatohepatitis: Inserting nuclear receptors into the circle

Authors

  • Chiara Gabbi M.D., Ph.D.,

    1. Center for Nuclear Receptors and Cell Signaling University of Houston Houston, TX
    2. Department of Biosciences and Nutrition Karolinska Institutet Stockholm, Sweden
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  • Jan-Åke Gustafsson M.D., Ph.D

    1. Center for Nuclear Receptors and Cell Signaling University of Houston Houston, TX
    2. Department of Biosciences and Nutrition Karolinska Institutet Stockholm, Sweden
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  • Potential conflict of interest: Nothing to report.

To the Editor:

We read with great interest the article by Tanaka et al.1 showing high serum levels of tauro-β-muricholic and taurocholic acid in two animal models of nonalcoholic steatohepatitis (NASH). Hepatic expression of transporters of bile acids from the circulation to the liver (Slc10a1/Slco1a1) was decreased, whereas those transporters that transfer bile acids to the blood (Abcc1/4) were increased. Given that canalicular bile acid pumps (Abcc2/Abcb11) were not significantly affected, this finding raises a crucial question: What is the hepatic bile acid concentration in NASH? If there is a decrease in liver bile acid content, one would expect a vicious circle aggravating NASH (Fig. 1).

Figure 1.

Autoregenerating vicious circle of nonalcoholic steatohepatitis. FXR, farnesoid x receptor; SHP, small heterodimer partner; SREBP-1c, sterol regulatory element binding protein-1c; TG, triglyceride; TGFβ, transforming growth factor β; TNFα, tumor necrosis factor α. Slc10a1, sodium/taurocholate transport protein; Slco, solute carrier organic anion transporter family member; Abcc, ATP-binding cassette sub- family C.

Bile acids are ligands for farnesoid x receptor (FXR), which through its regulation of small heterodimer partner inhibits the transcriptional activation of sterol regulatory element binding protein-1c (SREBP-1c). SREBP1c stimulates fatty acid synthesis. Thus inhibition of SREBP1-c via bile-acid activation of FXR results in a reduction of fatty liver.2 Moreover, activated FXR has potent anti-inflammatory and antifibrotic actions.3

The finding of Tanaka et al. may have revealed a hitherto unrecognized vicious circle around NASH (Fig. 1), starting with diet-induced lipid accumulation and tumor necrosis factor α/transforming growth factor β inflammatory cascade, leading to a possible reduction in bile acid content of the liver. Decreased ligand activation of FXR leads to triglyceride accumulation, inflammation, and regeneration of the noxious circle.

Interestingly, all of the pharmacological approaches capable of interrupting this vicious circle (i.e., by increasing the bile acid pool4 or inducing the expression of CYP7A1, the rate limiting enzyme in bile acid synthesis) have been shown to be beneficial for fatty liver and for NASH,5, 6 both in rodents and in humans.

In conclusion, the measurement of hepatic bile acids in NASH is important to clarify the pathogenesis of NASH and identify new therapeutic options.

Chiara Gabbi M.D., Ph.D.* †, Jan-Åke Gustafsson M.D., Ph.D* †, * Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, † Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Sweden.

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