PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation.
The role of the endoplasmic reticulum stress-regulated kinase, PERK, in mammary gland function was assessed through generation of a targeted deletion in mammary epithelium. Characterization revealed that PERK is required for functional maturation of milk-secreting mammary epithelial cells. PERK-dependent signaling contributes to lipogenic differentiation in mammary epithelium, and perk deletion inhibits the sustained expression of lipogenic enzymes FAS, ACL, and SCD1. As a result, mammary tissue has reduced lipid content and the milk produced has altered lipid composition, resulting in attenuated pup growth. Consistent with PERK-dependent regulation of the lipogenic pathway, loss of PERK inhibits expression of FAS, ACL, and SCD1 in immortalized murine embryonic fibroblasts when cultured under conditions favoring adipocyte differentiation. These findings implicate PERK as a physiologically relevant regulator of the lipogenic pathway.
The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Philadelphia, PA 19104, USA.
Ekaterina
E
Bobrovnikova-Marjon
Georgia
G
Hatzivassiliou
Christina
C
Grigoriadou
Margarita
M
Romero
Douglas R
DR
Cavener
Craig B
CB
Thompson
J Alan
JA
Diehl
D017667:Adipocytes / Q000166:cytology* / Q000201:enzymology*; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004789:Enzyme Activation; D004848:Epithelium / Q000201:enzymology / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D050155:Lipogenesis; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000201:enzymology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; D019892:eIF-2 Kinase; C506119:Insig1 protein, mouse