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


CONCLUSIONS
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.
Peyer
Anne-Kathrin
AK
Division of Pharmacology and Neurobiology, Biozentrum, University of Basel, Basel, Switzerland.
Jung
Diana
D
Beer
Markus
M
Gnerre
Carmela
C
Keogh
Adrian
A
Stroka
Deborah
D
Zavolan
Mihaela
M
Meyer
Urs-A
UA
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006418:Heme / Q000096:biosynthesis*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D000624:5-Aminolevulinate Synthetase; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D006418:Heme; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated