title: Absence of functional peroxisomes does not lead to deficiency of enzymes involved in cholesterol biosynthesis.
abstract: To unravel the conflicting data concerning the dependence of human cholesterol biosynthesis on functional peroxisomes, we determined activities and levels of selected enzymes involved in cholesterol biosynthesis in livers of PEX5 knockout mice, a well-characterized model for human Zellweger syndrome. We found that all enzymes measured, including putative peroxisomal enzymes, are at least as active in the peroxisome-deficient Zellweger mice as in control mice, indicating that mislocalization of enzymes to the cytosol does not lead to decreased activity or degradation. Prompted by these results, we re-examined this aspect in human subjects by specific enzyme activity measurements and immunoblotting with highly specific antisera. Our results show that the previously reported deficiencies of mevalonate kinase and phosphomevalonate kinase activity in livers from human Zellweger patients reflect the bad condition of the livers, rather than mislocalization to the cytosol. Our data provide an explanation for the conflicting findings in the literature and show that great care should be taken in the interpretation of data obtained in postmortem material.
authors.affiliation: Laboratory for Genetic Metabolic Diseases (F0-224), Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
authors.forename: Sietske
authors.initials: S
authors.lastname: Hogenboom
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Romeijn
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: Myriam
authors.initials: M
authors.lastname: Baes
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004795:Enzyme Stability; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D015151:Immunoblotting / Q000379:methods; D008099:Liver / Q000201:enzymology*; D051379:Mice; D020675:Peroxisomes / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism; D015211:Zellweger Syndrome / Q000378:metabolism*
chemical_list: D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D017856:Phosphotransferases (Phosphate Group Acceptor); C022371:phosphomevalonate kinase; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase