Symposium review: Amino acid uptake by the mammary glands: Where does the control lie?

Abstract

Milk protein yield responses to changes in the profile of essential amino acids absorbed by the gastrointestinal tract or circulating in blood plasma do not follow the classic limiting amino acid response, in part because of an ability of the mammary glands to modify their blood flow rate and net clearance of amino acids out of plasma. The hypothesis that mammary blood flow is locally regulated to maintain ATP balance accounts for observed changes in flow due to postruminal glucose, insulin, and essential amino acid (EAA) infusions. An additional hypothesis that net mammary uptakes of metabolites from blood are affected by perturbations in their respective arterial concentrations and the rate of mammary blood flow also appears to hold for the energy metabolites glucose, acetate, β-hydroxybutyrate, and fatty acids. However, net EAA uptakes by the mammary glands are poorly predicted by models considering arterial concentrations and blood flow rates only. Evidence points to intramammary protein synthesis and secretion as the determinant of net EAA uptake. The intracellular signaling network anchored by the mechanistic target of rapamycin complex 1 stands as an excellent candidate to explain nutritional effects on milk protein synthesis because it integrates information on physiological and nutritional state to affect protein synthesis and cell metabolism, growth, proliferation, and differentiation in many cell types. In mammary cells in vitro and in vivo, the mechanistic target of rapamycin complex 1, integrated stress response, and glycogen synthase kinase-3 networks that contribute to regulation of initiation of mRNA translation are responsive to acute changes in nutrient supply and EAA profile. However, after several days of postruminal infusion of balanced and imbalanced EAA profiles, these signaling networks do not appear to continue to account for changes in milk protein yields. Gene expression evidence suggests that regulation of components of the unfolded protein response that control biogenesis of the endoplasmic reticulum and differentiation of a secretory phenotype may contribute to effects of nutrition on milk protein yield. Connections between early signaling events and their long-term consequences should be sought.

Phosphorylation of AKT serine/threonine kinase and abundance of milk protein synthesis gene networks in mammary tissue in response to supply of methionine in periparturient Holstein cows

“…The upregulation (P ≤ 0.03) of the ER stress response genes XBP1 and ATF6 coupled with the downregulation (P ≤ 0.04) of PPP1R15A (Table 4) in cows fed Met suggested an association between enhanced Met supply and ER mechanisms that are important for mammary secretory cell function (Cant et al, 2018). However, the lack of difference in phosphorylation status of EIF2A (P = 0.26; Table 1) between Met and control cows seems to cast doubt on that association.…”

“…The quantitative (q)PCR was performed as described previously (Osorio et al, 2014) to determine relative mRNA abundance of target genes. The genes for study encompassed a subset of those measured by Bionaz and Loor (2011) in bovine mammary tissue across the lactation cycle, and those proposed by Cant et al (2018) as playing a key role in the nutritional regulation of milk protein synthesis. RPS9, RPS15, and UXT were selected as the internal control genes to normalize mRNA abundance data (Bionaz and Loor, 2007).…”

“…The importance of proper dietary balancing of EAA, and Met in particular, for milk protein synthesis in dairy cows was recently underscored by a large meta-analysis of published data (Lean et al, 2018). However, despite substantial work on the regulation of milk protein synthesis, knowledge of the intracellular signaling networks and their connections is in its infancy (Cant et al, 2018).…”

“…In the mammary gland, a clear relationship is present at the molecular level between EAA availability and insulin signaling on milk protein synthesis through changes in gene network expression (Bionaz and Loor, 2011;Loor et al, 2013), activity of the mechanistic tar-Phosphorylation of AKT serine/threonine kinase and abundance of milk protein synthesis gene networks in mammary tissue in response to supply of methionine in periparturient Holstein cows 4265 get of rapamycin complex 1 (mTORC1) pathway and related proteins (Appuhamy et al, 2011), or both (Cant et al, 2018). The role of the endoplasmic reticulum (ER) in protein synthesis, transport, and processing is well established in most eukaryotic cells (Malhotra and Kaufman, 2007) and the upregulation of this pathway in bovine mammary tissue was observed during lactation (Invernizzi et al, 2012).…”

“…The role of the endoplasmic reticulum (ER) in protein synthesis, transport, and processing is well established in most eukaryotic cells (Malhotra and Kaufman, 2007) and the upregulation of this pathway in bovine mammary tissue was observed during lactation (Invernizzi et al, 2012). A recent review of the literature underscored the potential role of the components of the unfolded protein response (UPR) in the control of the cellular secretory phenotype that is often enhanced in response to EAA, glucose supply, or both (Cant et al, 2018).…”