Format

Send to

Choose Destination
Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Dec;1862(12):1469-1480. doi: 10.1016/j.bbalip.2017.09.003. Epub 2017 Sep 6.

Iron depletion induces hepatic secretion of biliary lipids and glutathione in rats.

Author information

1
Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Czech Republic.
2
Department of Medical Biochemistry, Charles University, Faculty of Medicine in Hradec Kralove, Czech Republic.
3
Department of Biological and Medical Sciences, Charles University, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
4
Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Czech Republic; Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
5
Department of Pharmacology and Toxicology, Charles University, Faculty of Pharmacy in Hradec Kralove, Czech Republic.
6
Department of Medical Biochemistry and Laboratory Diagnostics, Charles University, 1st Faculty of Medicine, Prague, Czech Republic.
7
Department of Medical Biochemistry and Laboratory Diagnostics, Charles University, 1st Faculty of Medicine, Prague, Czech Republic; 4th Department of Internal Medicine, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
8
Department of Pharmacology, Charles University, Faculty of Medicine in Hradec Kralove, Czech Republic. Electronic address: micuda@lfhk.cuni.cz.

Abstract

Iron depletion (ID) has been shown to induce the liver expression of Cyp7a1, the rate-limiting enzyme initiating conversion of cholesterol to bile acids (BA), although the effect on bile acids metabolism and bile production is unknown. Therefore, we investigated changes in bile secretion and BA synthesis during diet-induced iron depletion (ID) in rats. ID increased bile flow along with augmented biliary excretion of bile acids, glutathione, cholesterol and phospholipids. Accordingly, we found transcriptional upregulation of the Cyp7a1, Cyp8b1, and Cyp27a1 BA synthetic enzymes, as well as induction of the Abcg5/8 cholesterol transporters in ID rat livers. In contrast, intravenous infusion of 3H-taurocholate failed to elicit any difference in biliary secretion of this compound in the ID rats. This corresponded with unchanged expression of canalicular rate-limiting transporters for BA as well as glutathione. We also observed that ID substantially changed the spectrum of BA in bile and decreased plasma concentrations of BA and cholesterol. Experiments with differentiated human hepatic HepaRG cells confirmed human CYP7A1 orthologue upregulation resulting from reduced iron concentrations. Results employing a luciferase reporter gene assay suggest that the transcriptional activation of the CYP7A1 promoter under ID conditions works independent of farnesoid X (FXR), pregnane X (PXR) and liver X (LXRα) receptors activation. It can be concluded that this study characterizes the molecular mechanisms of modified bile production as well as cholesterol as along with BA homeostasis during ID. We propose complex upregulation of BA synthesis, and biliary cholesterol secretion as the key factors affected by ID.

KEYWORDS:

Abcg5/8; Bile acid synthesis; Bile production; Cyp7a1; Iron depletion

PMID:
28888833
DOI:
10.1016/j.bbalip.2017.09.003
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center