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

Abstract

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 acidactivated 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. (HEPATOLOGY 2007;46:1960-1970

Regulation of human class I alcohol dehydrogenases by bile acids

“…4 ). Such a species-dependent regulation has also been observed for other human FXR target genes, including syndecan-1 ( 36 ), fi brinogen ( 37 ), ␣ A-crystallin ( 38 ), peroxisome proliferator-activated receptor ␣ ( 39 ), hepatic lipase ( 40 ), ALAS1 ( 29 ), fetuin-b ( 41 ), and PCSK9 ( 42 ). The reason for such expansion in the repertoire of FXR targets in humans, compared with rodents, remains obscure.…”

“…5A , IR1 elements in ADH1A , ADH1B , and ADH1C promoters differ from 2, 3, and 4 nucleotides, respectively, from the consensus FXRE. The presence of a T at position 3 and a C at position 10 of the IR1 element are permissive (e.g., FXREs of FGF19 and ALAS1 , respectively) ( 10,29 ). In contrast, A into G conversion at the sixth position, as it occurs in the ADH1C element, is detrimental to receptor binding ( 27,28 ).…”

Egr-1 regulates the transcriptional repression of mouse δ-aminolevulinic acid synthase 1 by heme

“…Other investigators (Fraser et al, 2003;Handschin et al, 2005;Peyer et al, 2007) have shown that several transcription factors including nuclear receptors CAR, PXR, FXR and HNF4α as well as the coactivator PGC-1α mediate the transcriptional regulation of ALAS1 to various stumuli such as fasting, or upon the exposure to endo-and xenobiotics. Since it is recently reported that ALAS1 expression is repressed by heme at a transcriptional level, mediating by recently identified nuclear receptors such as Rev-erbα (Yin et al, 2007;Wu et al, 2009), we tried to identify the site of the enhancer region involved of nuclear receptors in down-regulation of the expression of the mouse ALAS1 transcription, which is exerted by the end product heme.…”

Relationship between circadian oscillations of Rev-erbα expression and intracellular levels of its ligand, heme

“…More likely is the possibility that intracellular heme levels offer a point of access for modification of the characteristics of the circadian rhythm. There are a number of examples of regulatory inputs that modify Alas1 expression including bile acids [24], nutritional status via PGC-1α [25], and xenobiotics [26,27]. Additionally, regulation of heme oxygenase, which controls heme degradation, is another mechanism that may be used to modify the mammalian clock via modulation of intracellular heme levels.…”