title: Disturbed cholesterol homeostasis in a peroxisome-deficient PEX2 knockout mouse model.
abstract: 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.
authors.affiliation: Department of Biology, San Diego State University, San Diego, California 92182, USA.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Kovacs
authors.forename: Janis E
authors.initials: JE
authors.lastname: Shackelford
authors.forename: Khanichi N
authors.initials: KN
authors.lastname: Tape
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Richards
authors.forename: Phyllis L
authors.initials: PL
authors.lastname: Faust
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fliesler
authors.forename: Skaidrite K
authors.initials: SK
authors.lastname: Krisans
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D004195:Disease Models, Animal; D006706:Homeostasis / Q000502:physiology; D007668:Kidney / Q000201:enzymology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000074428:Peroxisomal Biogenesis Factor 2; D020675:Peroxisomes / Q000378:metabolism*; D013154:Spleen / Q000201:enzymology; D015211:Zellweger Syndrome / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D008565:Membrane Proteins; C000614231:PEX2 protein, mouse; D000074428:Peroxisomal Biogenesis Factor 2; D002784:Cholesterol