title: Adipophilin regulates maturation of cytoplasmic lipid droplets and alveolae in differentiating mammary glands.
abstract: Milk lipids originate by secretion of triglyceride-rich cytoplasmic lipid droplets (CLDs) from mammary epithelial cells. Adipophilin (ADPH)/Plin2, a member of the perilipin family of CLD binding proteins, is hypothesized to regulate CLD production in these cells during differentiation of the mammary gland into a secretory organ. We tested this hypothesis by comparing CLD accumulation in differentiating mammary glands of wild-type and ADPH-deficient mice. ADPH deficiency did not prevent CLD formation; however, it disrupted the increase in CLD size that normally occurs in differentiating mammary epithelial cells. Failure to form large CLDs in ADPH-deficient mice correlated with localization of adipose triglyceride lipase (ATGL) to the CLD surface, suggesting that ADPH promotes CLD growth by inhibiting lipolytic activity. Significantly, mammary alveoli also failed to mature in ADPH-deficient mice, and pups born to these mice failed to survive. The possibility that CLD accumulation and alveolar maturation defects in ADPH-deficient mice are functionally related was tested by in vivo rescue experiments. Transduction of mammary glands of pregnant ADPH-deficient mice with adenovirus encoding ADPH as an N-terminal GFP fusion protein prevented ATGL from localizing to CLDs and rescued CLD size and alveolar maturation defects. Collectively, these data provide direct in vivo evidence that ADPH inhibition of ATGL-dependent lipolysis is required for normal CLD accumulation and alveolar maturation during mammary gland differentiation. We speculate that impairing CLD accumulation interferes with alveolar maturation and lactation by disrupting triglyceride homeostasis in mammary epithelial cells.
authors: Graduate Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Tanya D
authors: TD
authors: Russell
authors: Jerome
authors: J
authors: Schaack
authors: David J
authors: DJ
authors: Orlicky
authors: Carol
authors: C
authors: Palmer
authors: Benny Hung-Junn
authors: BH
authors: Chang
authors: Lawrence
authors: L
authors: Chan
authors: James L
authors: JL
authors: McManaman
mesh_terms: D000818:Animals; D002364:Caseins / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007774:Lactation / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000070780:Perilipin-2; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D002364:Caseins; D049452:Green Fluorescent Proteins; D008049:Lipase; D008565:Membrane Proteins; D000070780:Perilipin-2; D011993:Recombinant Fusion Proteins; C000602983:Plin2 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases