XBP1 Regulates the Biosynthetic Capacity of the Mammary Gland During Lactation by Controlling Epithelial Expansion and Endoplasmic Reticulum Formation

Abstract

Cells composing the mammary secretory compartment have evolved a high capacity to secrete not only proteins but also triglycerides and carbohydrates. This feature is illustrated by the mouse, which can secrete nearly twice its own weight in milk proteins, triglycerides and lactose over a short 20-day lactation. The coordination of synthesis and export of products in other secretory cells is orchestrated in part by the transcription factor X-box binding protein 1 (XBP1). To assess the role of XBP1 in mammary epithelial cells (MEC), we studied floxed XBP1 female mice lacking (wild type; WT) or expressing the Cre recombinase under the control of the ovine β-lactoglobulin promoter (ΔXBP1(MEC)). Pregnant ΔXBP1(MEC) females had morphologically normal mammary development and gave birth to the same number of pups as WT mice. Their litters, however, suffered a weight gain deficit by lactation day 3 (L3)3 that grew to 80% by L14. ΔXBP1(MEC) dams had only modest changes in milk composition (-21% protein, +24% triglyceride) and in the expression of associated genes in isolated MEC. By L5, WT glands were fully occupied by dilated alveoli, whereas ΔXBP1(MEC) glands contained fewer, mostly unfilled alveoli and retained a prominent adipocyte population. The smaller epithelial compartment in ΔXBP1(MEC) glands was explained by lower MEC proliferation and increased apoptosis. Finally, endoplasmic reticulum ribbons were less abundant in ΔXBP1(MEC) at pregnancy day 18 and failed to increase in abundance by L5. Collectively, these results show that XBP1 is required for MEC population expansion during lactation and its ability to develop an elaborate endoplasmic reticulum compartment.

Transcriptional profiling of swine mammary gland during the transition from colostrogenesis to lactogenesis using RNA sequencing

“…Considering those transcription regulators in the IPA findings that overlap in the last 2 time comparisons ( p -value cutoff ≤0.01 and activation z-score ≥ ± 2) the results supported the suggestion that SREBP1 and XBP1 are pivotal in the transition from colostrogenesis to lactogenesis in swine mammary gland. They likely act on regulation of lipid synthesis [ 129 ] and morphological mammary development [ 130 ], respectively.…”

“…XBP1 is also implicated as a positive regulator of both lipogenesis and VLDL (very low density lipoprotein) secretion in hepatocytes [ 143 , 144 ]. Recently, in murine, it was shown that XBP1 is required for MEC population expansion during lactation, enhancing the development of an elaborate endoplasmic reticulum compartment [ 130 ] and playing a central role in the coordination of synthesis and export of products in mammary epithelial cells [ 145 ].…”

Exogenous essential amino acids stimulate an adaptive unfolded protein response in the mammary glands of lactating cows

“…Mammary- Representative blots for the abundance of phosphorylated (p) and total signaling proteins and GAPDH from skeletal muscle of lactating dairy cows after 5 d of abomasal infusion of 0.9% saline (SAL) or complete mixtures of EAA equivalent to 1,500 and 2,000 g/d casein, with or without the inclusion of 1,000 g/d glucose (1.5EAA, 2EAA, 1.5+GLC, and 2+GLC, respectively). S6K = 70-kDa ribosomal protein S6 kinase; eIF2 = eukaryotic initiation factor 2B, ε subunit; Akt = protein kinase B; AMPKα = AMP-activated protein kinase, α subunit; eIF2α = eukaryotic initiation factor 2, α subunit; 4EBP1 = eIF4E-binding protein 1. specific deletion of the XBP1 gene in mice severely curtails the increase in ER abundance and complexity that occurs in mammary epithelial cells at the onset of lactation (Davis et al, 2016). These functions of the 3 arms of the UPR serve to increase ER functionality unless the ER stress becomes too severe, at which point CHOP initiates apoptosis.…”

“…Splicing of XBP1 is required for terminal differentiation of progenitor cells into cells that specialize in secretory activities, such as plasma cells that secrete antibodies (Reimold et al, 2001) and gastric zymogenic cells that secrete digestive enzymes (Huh et al, 2010). In the mammary glands, conditional knockout of XBP1 not only affected ER expansion but also suppressed proliferation and stimulated apoptosis during lactation, leading to a reduced population of epithelial cells and impairment of milk synthesis (Davis et al, 2016). Interestingly, XBP1 ablation resulted in overexpression of DDIT3, implicating XBP1 directly in the suppression of CHOP-mediated apoptosis.…”

New Insights of Mammary Gland During Different Stages of Development

“…It promotes the lobuloalveolar development by indirectly reducing the cellular ROS (reactive oxygen species) level and enhancing the expression of milk protein genes as well as proliferative genes for alveoli development. Another protein XBP1 (transcription factor) regulates biosynthesis in MECs by influencing epithelial expansion and formation of estrogen in MECs [48].…”