Potential conflict of interest: Nothing to report.
Bile acids in nonalcoholic steatohepatitis: Inserting nuclear receptors into the circle†
Article first published online: 31 OCT 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 5, pages 2008–2009, November 2012
How to Cite
Gabbi, C. and Gustafsson, J.-Å. (2012), Bile acids in nonalcoholic steatohepatitis: Inserting nuclear receptors into the circle. Hepatology, 56: 2008–2009. doi: 10.1002/hep.25812
- Issue published online: 31 OCT 2012
- Article first published online: 31 OCT 2012
- Accepted manuscript online: 26 APR 2012 05:42AM EST
- Manuscript Accepted: 10 APR 2012
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).
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.
- 1Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis [published online ahead of print January 30, 2012]. HEPATOLOGY. doi: 10.1002/hep.25630., , , , .
- 2Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004; 113: 1408-1418., , , , , , et al.
- 3The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 2004; 127: 1497-1512., , , , , , et al.
- 4A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011; 54: 1011-1019., , , , , , et al.
- 5Prevention and treatment of obesity, insulin resistance, and diabetes by bile acid-binding resin. Diabetes 2007; 56: 239-247., , , , , , et al.
- 6Treatment of preestablished diet-induced fatty liver by oral fatty acid-bile acid conjugates in rodents. Eur J Gastroenterol Hepatol 2008; 20: 1205-1213., , , , , , et al.
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.