Promoter rearrangements cause species-specific hepatic regulation of the glyoxylate reductase/hydroxypyruvate reductase gene by the peroxisome proliferator-activated receptor alpha.
In liver, the glyoxylate cycle contributes to two metabolic functions, urea and glucose synthesis. One of the key enzymes in this pathway is glyoxylate reductase/hydroxypyruvate reductase (GRHPR) whose dysfunction in human causes primary hyperoxaluria type 2, a disease resulting in oxalate accumulation and formation of kidney stones. In this study, we provide evidence for a transcriptional regulation by the peroxisome proliferator-activated receptor alpha (PPARalpha) of the mouse GRHPR gene in liver. Mice fed with a PPARalpha ligand or in which PPARalpha activity is enhanced by fasting increase their GRHPR gene expression via a peroxisome proliferator response element located in the promoter region of the gene. Consistent with these observations, mice deficient in PPARalpha present higher plasma levels of oxalate in comparison with their wild type counterparts. As expected, the administration of a PPARalpha ligand (Wy-14,643) reduces the plasma oxalate levels. Surprisingly, this effect is also observed in null mice, suggesting a PPARalpha-independent action of the compound. Despite a high degree of similarity between the transcribed region of the human and mouse GRHPR gene, the human promoter has been dramatically reorganized, which has resulted in a loss of PPARalpha regulation. Overall, these data indicate a species-specific regulation by PPARalpha of GRHPR, a key gene of the glyoxylate cycle.
Genolet
Raphael
R
Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.
Kersten
Sander
S
Braissant
Olivier
O
Mandard
Stéphane
S
Tan
Nguan Soon
NS
Bucher
Philipp
P
Desvergne
Béatrice
B
Michalik
Liliane
L
Wahli
Walter
W
D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D006801:Humans; D050537:Hydroxypyruvate Reductase; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D047493:PPAR alpha / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
D017931:DNA Primers; D047493:PPAR alpha; D004247:DNA; D000429:Alcohol Oxidoreductases; C020830:glyoxylate reductase; D050537:Hydroxypyruvate Reductase