Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene.
The endoplasmic reticulum (ER) enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which converts HMG-CoA to mevalonate, catalyzes the ratelimiting step in cholesterol biosynthesis. Because this mevalonate pathway also produces several non-sterol isoprenoid compounds, the level of HMG-CoA reductase activity may coordinate many cellular processes and functions. We used gene targeting to knock out the mouse HMG-CoA reductase gene. The heterozygous mutant mice (Hmgcr+/-) appeared normal in their development and gross anatomy and were fertile. Although HMG-CoA reductase activities were reduced in Hmgcr+/- embryonic fibroblasts, the enzyme activities and cholesterol biosynthesis remained unaffected in the liver from Hmgcr+/- mice, suggesting that the haploid amount of Hmgcr gene is not rate-limiting in the hepatic cholesterol homeostasis. Consistently, plasma lipoprotein profiles were similar between Hmgcr+/- and Hmgcr+/+ mice. In contrast, the embryos homozygous for the Hmgcr mutant allele were recovered at the blastocyst stage, but not at E8.5, indicating that HMG-CoA reductase is crucial for early development of the mouse embryos. The lethal phenotype was not completely rescued by supplementing the dams with mevalonate. Although it has been postulated that a second, peroxisome-specific HMG-CoA reductase could substitute for the ER reductase in vitro, we speculate that the putative peroxisomal reductase gene, if existed, does not fully compensate for the lack of the ER enzyme at least in embryogenesis.
Ohashi
Ken
K
Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Osuga
Jun-ichi
J
Tozawa
Ryuichi
R
Kitamine
Tetsuya
T
Yagyu
Hiroaki
H
Sekiya
Motohiro
M
Tomita
Sachiko
S
Okazaki
Hiroaki
H
Tamura
Yoshiaki
Y
Yahagi
Naoya
N
Iizuka
Yoko
Y
Harada
Kenji
K
Gotoda
Takanari
T
Shimano
Hitoshi
H
Yamada
Nobuhiro
N
Ishibashi
Shun
S
D000483:Alleles; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004622:Embryo, Mammalian / Q000473:pathology; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006903:Hydroxymethylglutaryl CoA Reductases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D018811:Maternal Exposure; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011247:Pregnancy; D011270:Pregnancy, Animal; D013997:Time Factors
D008074:Lipoproteins; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid