Characterization of transgenic rats constitutively expressing vitamin D-24-hydroxylase gene.
Vitamin D-24-hydroxylase (CYP24) is one of the enzymes responsible for vitamin D metabolism. CYP24 catalyzes the conversion of 25-hydroxyvitamin D(3) [25(OH)D(3)] to 24,25-dihydroxyvitamin D(3) [24,25(OH)(2)D(3)] in the kidney. CYP24 is also involved in the breakdown of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the active form of vitamin D(3). In this study, we generated transgenic (Tg) rats constitutively expressing CYP24 gene to investigate the biological role of CYP24 in vivo. Surprisingly, the Tg rats showed a significantly low level of plasma 24,25(OH)(2)D(3). Furthermore, the Tg rats developed albuminuria and hyperlipidemia shortly after weaning. The plasma lipid profile revealed that all lipoprotein fractions were elevated in the Tg rats. Also, the Tg rats showed atherosclerotic lesions in the aorta, which greatly progressed with high-fat and high-cholesterol feeding. These unexpected results suggest that CYP24 is involved in functions other than the regulation of vitamin D metabolism.
Kasuga
Hisao
H
Pharmaceutical Research Division, Takeda Chemical Industries, 17-85 Jusohonmachi, 2-chome, Yodokawa-ku, 532-8686, Osaka, Japan.
Hosogane
Naobumi
N
Matsuoka
Kunio
K
Mori
Ikuo
I
Sakura
Yasufumi
Y
Shimakawa
Kozo
K
Shinki
Toshimasa
T
Suda
Tatsuo
T
Taketomi
Shigehisa
S
D000419:Albuminuria / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology*; D006720:Homozygote; D006949:Hyperlipidemias / Q000235:genetics; D050356:Lipid Metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology*; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes; D014807:Vitamin D / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
D012333:RNA, Messenger; D014807:Vitamin D; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase