title: Peroxisomal membrane channel Pxmp2 in the mammary fat pad is essential for stromal lipid homeostasis and for development of mammary gland epithelium in mice.
abstract: To understand the functional role of the peroxisomal membrane channel Pxmp2, mice with a targeted disruption of the Pxmp2 gene were generated. These mice were viable, grew and bred normally. However, Pxmp2(-/-) female mice were unable to nurse their pups. Lactating mammary gland epithelium displayed secretory lipid droplets and milk proteins, but the size of the ductal system was greatly reduced. Examination of mammary gland development revealed that retarded mammary ductal outgrowth was due to reduced proliferation of epithelial cells during puberty. Transplantation experiments established the Pxmp2(-/-) mammary stroma as a tissue responsible for suppression of epithelial growth. Morphological and biochemical examination confirmed the presence of peroxisomes in the mammary fat pad adipocytes, and functional Pxmp2 was detected in the stroma of wild-type mammary glands. Deletion of Pxmp2 led to an elevation in the expression of peroxisomal proteins in the mammary fat pad but not in liver or kidney of transgenic mice. Lipidomics of Pxmp2(-/-)mammary fat pad showed a decrease in the content of myristic acid (C14), a principal substrate for protein myristoylation and a potential peroxisomal β-oxidation product. Analysis of complex lipids revealed a reduced concentration of a variety of diacylglycerols and phospholipids containing mostly polyunsaturated fatty acids that may be caused by activation of lipid peroxidation. However, an antioxidant-containing diet did not stimulate mammary epithelial proliferation in Pxmp2(-/-) mice. The results point to disturbances of lipid metabolism in the mammary fat pad that in turn may result in abnormal epithelial growth. The work reveals impaired mammary gland development as a new category of peroxisomal disorders.
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O Box 3000, FI-90014 Oulu, Finland.
authors.forename: Miia H
authors.initials: MH
authors.lastname: Vapola
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O Box 3000, FI-90014 Oulu, Finland.
authors.forename: Aare
authors.initials: A
authors.lastname: Rokka
authors.affiliation: Department of Pathology and Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Raija T
authors.initials: RT
authors.lastname: Sormunen
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, FI-70211 Kuopio, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.affiliation: Theodor-Boveri-Institut fȕr Biowissenschaften (Biocentrum) der Universität Wurzburg, D-97074 Wurzburg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Schmitz
authors.affiliation: Theodor-Boveri-Institut fȕr Biowissenschaften (Biocentrum) der Universität Wurzburg, D-97074 Wurzburg, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Conzelmann
authors.affiliation: Georgetown University Medical Center, Department of Oncology, Washington, DC 20057, USA.
authors.forename: Anni
authors.initials: A
authors.lastname: Wärri
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O Box 3000, FI-90014 Oulu, Finland.
authors.forename: Silke
authors.initials: S
authors.lastname: Grunau
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O Box 3000, FI-90014 Oulu, Finland. Electronic address: vasily.antonenkov@oulu.fi.
authors.forename: Vasily D
authors.initials: VD
authors.lastname: Antonenkov
authors.affiliation: Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, P.O Box 3000, FI-90014 Oulu, Finland. Electronic address: kalervo.hiltunen@oulu.fi.
authors.forename: J Kalervo
authors.initials: JK
authors.lastname: Hiltunen
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry; D004847:Epithelial Cells / Q000166:cytology; D005227:Fatty Acids / Q000737:chemistry; D005260:Female; D006706:Homeostasis; D007774:Lactation; D050356:Lipid Metabolism; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020675:Peroxisomes / Q000378:metabolism*; D010641:Phenotype; D011073:Polyamines / Q000737:chemistry; D013347:Subcellular Fractions; D013997:Time Factors
chemical_list: D001647:Bile Acids and Salts; D005227:Fatty Acids; D008565:Membrane Proteins; D011073:Polyamines; C489786:Pxmp2 protein, mouse
keywords: Lipid metabolism; Mammary glands; Membrane channels; Peroxisomes; Pxmp2