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Molecular and Cellular Biology, January 2004, p. 1-13, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.1-13.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disturbed Cholesterol Homeostasis in a Peroxisome-Deficient PEX2 Knockout Mouse Model

Werner J. Kovacs,1 Janis E. Shackelford,1 Khanichi N. Tape,1 Michael J. Richards,2 Phyllis L. Faust,3 Steven J. Fliesler,2 and Skaidrite K. Krisans1*

Department of Biology, San Diego State University, San Diego, California 92182,1 Saint Louis University Eye Institute and Department of Pharmacological and Physiological Sciences, Saint Louis University School of Medicine, St. Louis, Missouri 63104,2 Department of Pathology, Columbia University, New York, New York 100273

Received 27 June 2003/ Returned for modification 2 September 2003/ Accepted 18 September 2003

We evaluated the major pathways of cholesterol regulation in the peroxisome-deficient PEX2-/- mouse, a model for Zellweger syndrome. Zellweger syndrome is a lethal inherited disorder characterized by severe defects in peroxisome biogenesis and peroxisomal protein import. Compared with wild-type mice, PEX2-/- mice have decreased total and high-density lipoprotein cholesterol levels in plasma. Hepatic expression of the SREBP-2 gene is increased 2.5-fold in PEX2-/- mice and is associated with increased activities and increased protein and expression levels of SREBP-2-regulated cholesterol biosynthetic enzymes. However, the upregulated cholesterogenic enzymes appear to function with altered efficiency, associated with the loss of peroxisomal compartmentalization. The rate of cholesterol biosynthesis in 7- to 9-day-old PEX2-/- mice is markedly increased in most tissues, except in the brain and kidneys, where it is reduced. While the cholesterol content of most tissues is normal in PEX2-/- mice, in the knockout mouse liver it is decreased by 40% relative to that in control mice. The classic pathway of bile acid biosynthesis is downregulated in PEX2-/- mice. However, expression of CYP27A1, the rate-determining enzyme in the alternate pathway of bile acid synthesis, is upregulated threefold in the PEX2-/- mouse liver. The expression of hepatic ATP-binding cassette (ABC) transporters (ABCA1 and ABCG1) involved in cholesterol efflux is not affected in PEX2-/- mice. These data illustrate the diversity in cholesterol regulatory responses among different organs in postnatal peroxisome-deficient mice and demonstrate that peroxisomes are critical for maintaining cholesterol homeostasis in the neonatal mouse.

* Corresponding author. Mailing address: Department of Biology, San Diego State University, 5500 Campanile Dr. LS-331, San Diego, CA 92182. Phone: (619) 594-5368. Fax: (619) 594-5676. E-mail: skrisans{at}sunstroke.sdsu.edu.

Molecular and Cellular Biology, January 2004, p. 1-13, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.1-13.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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