**3.2 Golgi's glucose transporters**

The first studies related to glucose transport to the Golgi of MEC concluded that this was mediated by GLUT and SGLT transporters, since the transport of monosaccharides was inhibited by phloretin and phlorizin, known inhibitors of both types of transporters [33]. These vesicles present stereospecificity for several monosaccharides, such as D-glucose, L-glucose, D-xylose, 2-deoxy-D-glucose, and D-fructose. Moreover, the vesicles showed low permeability for glucosamine, a substrate of the GLUT1 transporter; for this reason, we assume that another glucose transporter is involved in the incorporation of glucose into this organelle. A decade later, another GLUT was identified in Golgi vesicles of MEC of late-lactating mice through Western blotting and binding studies of cytochalasin B, co-localizing with 110-kDa coatomer-associated protein β-COP [19, 24]. Interestingly, the results revealed that there is a second cytochalasin B-sensitive glucose transporter, which could correspond to GLUT8, cloned after such studies [34, 35]. In our last study, we were able to identify GLUT8 in the Golgi of lactating MEC in mice, co-localized with LALB, 58 K Golgi protein, and Golgi membrane-associated protein 130 [5]. Additionally, SGLT1 was identified in the Golgi of MEC from lactating cows, but no functional studies have been performed [23]. As SGLT is an active transporter that mobilize glucose thanks to electrochemical sodium gradient at the plasma membrane, more studies related to ion gradient between cytoplasm and inside the Golgi should be performed to really know the contribution of this transporter to glucose uptake into the Golgi of MEC. In **Figure 3**, we show glucose transporters present in the Golgi of mammary epithelial cell and their association with lactose synthesis.

In summary, the reports highlight a variable increase in the expression of GLUT1, GLUT8, and GLUT12 in pregnancy and/or lactation in different models, including rodents and ruminants, but their responsibility in glucose uptake in the Golgi of mammary epithelial cells, an essential step to lactose synthesis, is not clear [8, 24, 36]. Moreover, although GLUT8 has been co-localized with Golgi proteins in MEC and in different compartments of endomembrane system in other cell types, GLUT1 has been found in the Golgi of MEC only in some of the species and strains studied, and its intracellular localization had been associated with mitochondria, which in not part of endomembrane system [5, 24, 33, 37]. In particular, GLUT8 has been found in late endosome and reticulum.

### **3.3 Lactose synthesis regulation**

The lactose synthesis depends principally on lactogenic hormones and glucose uptake in the Golgi of MEC. It starts in the first third of pregnancy, increasing

#### **Figure 3.**

*Glucose transporters in the Golgi of mammary epithelial cell associated with lactose synthesis. Distributions of glucose transporters in this organelle are detailed. MEC, mammary epithelial cells; GLUT, facilitative glucose transporter; LS, lactose synthase; LALB, lactalbumin; GS, galactosyltransferase.*

considerately after parturition, when placental sexual steroid hormones decrease and lactogenic hormones increase [30–32]. The principal lactogenic hormone is prolactin, which is stimulated by suckling. The milk production also has been associated with the removal of an inhibitory agent of secretory activity of MEC in milk. Other factors involved in milk production are light and sexual hormones. The increase in light photoperiod from 16 to 18 h increases milk production, due to prolactin via insulin-like growth factor (IGF-1) and somatotropin, whereas pregnancy decreases milk production, due to an increase in estrogens [8]. There is still controversy over the role of LS in milk production. In particular, LALB knockout mice were unable to produce milk, and lactogenic hormones change LALB expression only in particular species. For example, in humans, prolactin increases LALB mRNA, but in rabbits it decreases it, and in other species it does not produce any change [20, 24]. Also, it has been proposed that hexokinase and the different enzymes involved in glucose transformation to UDP-galactose are important for lactose synthesis [7].

As it has been described, the limiting stage in lactose synthesis is the availability of glucose in the Golgi [27], but a combination of lactogenic hormones failed to induce their expression in bovine mammary explants [22, 30]. There are not changes in GLUT8 or GLUT12 expression in response to insulin, leptin, growth hormone, or glucose, but estradiol and progesterone increase GLUT1 in MEC [15, 17, 19, 38]. GLUT1 was redistributed to an intracellular compartment, presumably the Golgi, in response to prolactin and hydrocortisone, associated with phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) pathways and STAT5 binding to its promotor [39–41]. The upregulation of GLUT1 in pregnancy and lactation also has been associated with an increase in serotonin via 5'adenosine monophosphate-activated protein kinase (AMPK) and hypoxia via HIF1α [22, 28]. On the other hand, serotonin increased GLUT8 in the mammary gland and hypoxia and lipopolysaccharide decrease it [10]. GLUT8 is internalized in response to insulin in trophodermic cells and changed its expression in insulin-sensitive tissues, such as the liver and kidney, but failed to produce effects in adipocytes and

**15**

*Lactose Synthesis*

**4. Conclusion**

**Acknowledgements**

**Conflict of interest**

**Nomenclature**

partial finance of this publication.

The authors declare no conflict of interest.

SWEET sugars will eventually be exported transporter

AMPK 5' adenosine monophosphate-activated protein kinase

SREBP sterol regulatory element-binding protein Km Michaelis-Menten kinetic constant β-COP 110-kDa coatomer-associated protein

MEC mammary epithelial cell GLUT facilitative glucose transporter SGLT sodium-glucose transporter

LALB lactalbumin LS lactose synthase

*DOI: http://dx.doi.org/10.5772/intechopen.91399*

neuroblast cells [42–44]. Some carbohydrates also produce changes in location and expression of GLUT8, i.e., glucose induces GLUT8 trafficking from the Golgi to the reticulum of hippocampal cells in rats and upregulates it in 3T3-L1 adipocytes [42, 45]. On the other hand, fructose downregulates GLUT8 expression in colon tissue and CaCo-2 colon carcinoma cells but increases its expression in hepatocytes,

Mammals rely exclusively on milk supply from the mammary gland to survive at an early age. The proliferation of mammary epithelial cells and mammary establishment depend on glucose supply to the gland, whereas lactose synthesis depends directly on glucose entry into the Golgi of MEC, which is conjugated with UDPgalactose by lactose synthase to produce the disaccharide lactose. MEC presents polarized expression of GLUT1, SGLT1, and GLUT12 in its plasma membrane and also expresses GLUT1, GLUT8, and SGLT1 in the Golgi. Hormones and oxygen tension regulate the expression of these transporters; however, further studies are necessary to explore the effects of light/dark cycles and suckling in their expression, since these are factors involved in milk production. Additionally, the kinetics of transporters involved in glucose uptake in the Golgi or cytoplasm of MEC also needs to be explored. Understanding the regulation and function of glucose transporters will be useful to improve efficiency of milk yield in both, humans and cattle.

The authors would like to thank Fredy Díaz of Interactive Biology Laboratory,

Concepción, Chile, for drawing the figures we designed and the Vice-Rectory for Research and Post-grade at Universidad Católica de la Santísima Concepción for

Faculty of Medicine at Universidad Católica de la Santísima Concepción,

where it is located in the plasma membrane [46–48]. GLUT8 promoter has a binding sequence to transcription factor NF1, which has been associated with the response of GLUT4 to insulin and cyclic adenosyl monophosphate (cAMP) [42, 49]. neuroblast cells [42–44]. Some carbohydrates also produce changes in location and expression of GLUT8, i.e., glucose induces GLUT8 trafficking from the Golgi to the reticulum of hippocampal cells in rats and upregulates it in 3T3-L1 adipocytes [42, 45]. On the other hand, fructose downregulates GLUT8 expression in colon tissue and CaCo-2 colon carcinoma cells but increases its expression in hepatocytes, where it is located in the plasma membrane [46–48]. GLUT8 promoter has a binding sequence to transcription factor NF1, which has been associated with the response of GLUT4 to insulin and cyclic adenosyl monophosphate (cAMP) [42, 49].
