Regulation of human liver delta-aminolevulinic acid synthase by bile acids

Peyer, Anne-Kathrin; Jung, Diana; Beer, Markus; Gnerre, Carmela; Keogh, Adrian; Stroka, Deborah; Zavolan, Mihaela; Meyer, Urs-A (2007). Regulation of human liver delta-aminolevulinic acid synthase by bile acids. Hepatology, 46(6), pp. 1960-70. Hoboken, N.J.: Wiley Interscience 10.1002/hep.21879

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Aminolevulinic acid synthase 1 (ALAS1) is the rate-limiting enzyme of heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target of the bile acid-activated nuclear receptor farnesoid X receptor (FXR). Experiments in primary human hepatocytes and in human liver slices showed that ALAS1 messenger RNA (mRNA) and activity is increased upon exposure to chenodeoxycholic acid (CDCA), the most potent natural FXR ligand, or the synthetic FXR-specific agonist GW4064. Moreover, overexpression of a constitutively active form of FXR further increased ALAS1 mRNA expression. In agreement with these observations, an FXR response element was identified in the 5' flanking region of human ALAS1 and characterized in reporter gene assays. A highly conserved FXR binding site (IR1) within a 175-bp fragment at -13 kilobases upstream of the transcriptional start site was able to trigger an FXR-specific increase in luciferase activity upon CDCA treatment. Site-directed mutagenesis of IR1 abolished this effect. Binding of FXR/retinoid acid X receptor heterodimers was demonstrated by mobility gel shift experiments. Conclusion: These data strongly support a role of bile acid-activated FXR in the regulation of human ALAS1 and, consequently, hepatic porphyrin and heme synthesis. These data also suggest that elevated endogenous bile acids may precipitate neuropsychiatric attacks in patients with acute hepatic porphyrias.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery

UniBE Contributor:

Keogh-Stroka, Deborah M.

ISSN:

0270-9139

ISBN:

17975826

Publisher:

Wiley Interscience

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:57

Last Modified:

04 May 2014 23:16

Publisher DOI:

10.1002/hep.21879

PubMed ID:

17975826

Web of Science ID:

000251471700034

URI:

https://boris.unibe.ch/id/eprint/24249 (FactScience: 47800)

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