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J. Biol. Chem., Vol. 278, Issue 44, 42936-42941, October 31, 2003

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Early Embryonic Lethality Caused by Targeted Disruption of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Gene^*

Ken Ohashi, Jun-ichi Osuga, Ryuichi Tozawa, Tetsuya Kitamine, Hiroaki Yagyu, Motohiro Sekiya, Sachiko Tomita, Hiroaki Okazaki, Yoshiaki Tamura, Naoya Yahagi, Yoko Iizuka, Kenji Harada, Takanari Gotoda¶, Hitoshi Shimano||, Nobuhiro Yamada||, and Shun Ishibashi**

From the Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, the Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, the ^¶Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo 162-0054, and the ^||Metabolism, Endocrinology and Atherosclerosis, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan

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.

Received for publication, July 7, 2003

^* This work was supported by grant-in-aid for Scientific Research 10557104 from the Ministry of Education, Science, and Culture, the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (OPSR), and Health Sciences Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare, Takeda Medical Research Foundation, and Yamnouchi Foundation for Research on Metabolic Disorders. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 81-285-58-7355; Fax: 81-285-40-6035; E-mail: ishibash{at}jichi.ac.jp.

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