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فیزیولوژی تولید و ترشح شیر Lactation Physiology (part 1) By: A. Riasi (PhD in Animal Nutrition & Physiology) At the end of this section student will be able to reply: What is the supportive system in udder? What is the forstenberg’s rosette in papilla mammae? What are the important parts of a secretory cell? Which barriers are between the circulatory primary substance and milk? What are the transporter systems in mammary epithelial cells? Where is the lactose production site in the alveolar epithelial cells? What are the pathways for milk fat globule transit and secretion from mammary epithelial cells? How is the de novo fatty acid synthesis in mammary cells? What is the milk fat depression syndrome? What is a mammary gland? Is modified sweat gland. Serves a reproductive function; nourishment of the neonate. Can repeatedly undergo growth, functional differentiation, and regression. Relies on same endocrine support for development and function. Example: gonadal steroids, prolactin, etc. What is the difference between the animal udder? Anterior (thoracic) Intermediate (abdominal) Posterior (inguinal) Total Goat, sheep, horse guinea pig 0 0 2 2 Cattle 0 0 4 4 Cat 2 2 4 8 Dog 4 2 2 or 4 8 or 10 Mouse 6 0 4 10 Rat 6 2 4 12 Pig 6 6 6 18 proboscideans, primates 2 0 0 2 Species www.wikipedia.org What is the difference between the animal udder? Cow: Four glands and four teats Sheep and goats: Two glands and two teats Sow: 12-14 teats and two glands per teat. Mare: Four glands and only two teats. The udder is a complex system A supportive system A secretory system composed of epithelial cells A duct system for storage and conveyance of milk Blood, lymph, and nerve systems The udder of cows The weight of empty cows udder is about 12-30 kg. The udder weight is affected by: Age Stage of lactation Amount of milk in the udder Inherited differences among cows The supportive system of udder There are seven tissues that provide support for the udder: Skin (covering the gland is only of very minor support) Superficial fascia or Areolar subcutaneous tissue Coarse areolar or cordlike tissue Subpelvic tendon Superficial layers of lateral suspensory ligament Deep lateral suspensory ligament Median Suspensory Ligament An illustrated view of the ligaments that permit udder suspension (Courtesy of Iowa State University) Teat structure Annular (cricoid) rings Furstenburg’s rosette Interior anatomy of the Mammary Gland The interior structure of mammary gland: Connective tissue (Stroma) Ductular system Secretory tissue Mammary duct system Secretory tissue (Adapted from Akers & Denbow, 2013) Mammary alveolus. This diagram illustrates the three dimensional structure of the mammary alveolus. The hollow center of the alveolus provide a space for the accumalation of milk components that have been synthesized and secreted by the secretory cells that compose the internal wall of the structure. The outside of the alveolus has a network of myoepithelial cells that contract in response of release of oxytocin at the time of milking. This forces stored milk into the terminal duct, which exits the lumen the alveolus. The milk progresses through larger ducts to be emptied at the nipple or teat end. (Adapted from Akers & Denbow) A photomicrograph of a developing mammary duct. Taken from a Holstein calf, this tissue stained with specific cytokeratin 18 (red, a marker specific for epithelial cells), CD10 (green , a marker of myoepithelial cells), and Ki67 (yellow, a protein produced in nuclei of cells that are about to divide). The tissue section is from a study to evaluate the effects of the ovary on ontogeny of myoepithelial cells in the bovine mammary gland. (Adapted from Akers & Denbow, 2103) Secretory tissue A lactating secretory cell is the basic unit of milk synthesis Milk precursors are taken from the blood into the cell The secretory cell have two kind of junctions with neighbor cells: Tight junction around the apical portion Gap junction in lateral portion Major component of a secretory epithelial cell Apical membrane Secretory vesicles Golgi apparatus Tight junction Rough Endoplasmic Reticulum Nucleus Lysosomes Cytoplasm Basement membrane Gap junction Smooth Endoplasmic Reticulum Basal and lateral membranes Milk synthesis and secretion The product of mammary gland depends on two mode of secretion: Apocrine Merocrine Other components are derived by passage of soluble molecules across (transcellular) and sometimes between (paracellular) the cells. Milk synthesis and secretion Physically, milk is a complex solution of: Salts Carbohydrates Miscellaneous compounds with dispersed proteins and protein aggregates Casein micelles Fat globules Milk osmolarity generally equals blood and the pH of 6.2-7.0. Milk synthesis and secretion During the established lactation, function of the mammary gland is closely linked with: Some hormones Growth factors Local tissue regulators Along with mammary cell-specific constituents, milk contains a myriad of minor components. Many of these molecules are important nutrients or regulators of the neonate. Milk synthesis and secretion Molecules are transported into the milk by several possible routes. Mammary epithelial cells are able to maintain substantial gradients for Na+, K+, and Cl− ions across the cell membrane. Concentrations of Na+ inside (~ 43 mM) the cells are typically lower than outside (150 mM). The gradient for K+ is the opposite (143 mM inside compared with 4.5 mM outside). Concentration of Cl− is higher inside the cells. Milk synthesis and secretion Milk is a rich source of calcium. The calcium in the milk exists as: Casein-bound calcium Calcium associated with various inorganic anions For example, citrate and phosphate Free calcium Milk synthesis and secretion The rate of calcium influx into the cell is matched by a corresponding uptake of calcium by cellular organelles. An ATP-dependent calcium pump on Golgi membranes The uptake of Ca by the epithelial cells probably dependent to: Parathyroid hormone-related protein 1,25-(OH)2 vitamin D3 Precursors of Milk Precursors of milk come from the blood stream and the primary substrates extracted from blood are: Glucose Amino acids Fatty acids Minerals Acetate * βHB * Precursors of Milk Several materials in milk come unchanged from the blood: Minerals Hormones Immunoglobulins Synthesis of milk proteins There are several specific systems for amino acids absorption through the basal membrane. Inside the cell, amino acids are covalently bound together to form proteins at the polysomes (Poly-ribosomes). Proteins sythesized at RER include: Casein β-lactoglobulin α-lactalbumin Membrane bound proteins Membrane boding enzymes Synthesis of milk proteins Synthesized proteins are transferred the golgi apparatues (GA). Casein is secreted as micelle, which is formed in the GA from: Casein molecules Calcium Phosphorus A: a submicelle; B: protruding chain; C: Calcium phosphate; D: κ-casein; E: phosphate groups Synthesis of milk lactose Glucose enters the cells via the basolateral membrane by specific transport system. Some glucose is converted to galactose in the cell. Both glucose and galactose enter the GA and react resulting in the formation of lactose. Synthesis of milk fat The sources of milk FA: Blood FA De novo FA Glycerol Monoacylglyceride (MAG) Acetate * β-hydroxybutyrate * Milk fat triglycerides are synthesized endoplasmic reticulum and form small droplet. on the smooth Synthesis of milk fat The protein coat on the milk fat globule membrane comprises: Mainly butyrophilin (BTN) * Xanthine oxidoreductase (XDH) * Adipophilin (ADPH)** Mucin 1 CD36 Periodic acid/Schiff PAS III FABP Pathways for milk fat globule transit and secretion from mammary epithelial cells Synthesis of milk fat The properties of milk fat: Milk fat composed of different fatty acids: Short chains (4-8 C) Medium chains (10-14 C) Long chains (≥16 C) Synthesis of milk fat The properties of milk fat: TAG (more than 95% of milk fat) DAG (2%) Phospholipids (1%) Cholesterol (0.5%) FFA (0.1%) Ether lipid, Fat soluble vitamins., etc. Synthesis of milk fat The properties of milk fat: Saturated FAs (~70%) Palmitic acid Myristic acid Stearic acid Monounsaturated FA (~25%) Oleic acid Vaccenic acis Polyunsaturated FA (~5%) Synthesis of milk fat There are two sources of FA for milk fat synthesis: The de novo FA synthesis in mammary epithelial cells Short chain (4-8 C) Medium chain (10-14 C) ~ 50% of 16 C Preformed FA uptake from blood circulation ~ 50% of 16 C > 16 C De novo fatty acid synthesis In ruminants, the substrates for de novo FA synthesis in mammary epithelial cells are: Acetate produced by rumen fermentation β- hydroxybutyrate produced by the rumen epithelium Preformed fatty acid uptake Long-chain FA taken up by the mammary gland are imported from plasma: Released from circulating lipoproteins by lipoprotein lipase NEFA bound to albumin There is evidence showing that the membrane transport of long- chain FA is a facilitated process. Some factors might play a role in FA uptake and transport: Cluster of differentiation 36 (CD36) Fatty acid binding protein 3 (FABP3) Properties of milk TAG Fatty acids are not esterified randomly to the sn-1, -2, and -3 positions of glycerol backbone. The distribution of FA is dependent on the distinct binding affinities of the acyltransferase enzymes for substrate FA. Transport of milk components Adapted from McManaman and Neville, 2003 Abbreviations: SV, secretory vesicle; RER, rough endoplasmic reticulum; BM, basement membrane; N, nucleus; PC, plasma cell; FDA, fat depleted adipocyte; JC, junctional complex containing the tight and adherens junctions; GJ, gap junction; ME, myoepithelial cell. Transport of milk components Pathway I depicts exocytotic for: Protein secretion by alveolar cells Water Lactose Oligosaccharides Phosphate Calcium Citrate Transport of milk components Pathway II depicts milk fat secretion. Milk lipids, primarily triacylgycerides and phospholipids, are synthesized in the smooth endoplasmic reticulum in the basal region of the cell. Newly synthesized lipid molecules form cytoplasmic lipid droplets and are secreted by a unique budding process (MFGs). Transport of milk components Milk fat globule membrane is known to contain numerous enzymes, including oxidases, reductases and hydrolases with relatively high specific activities. In particular milk fat globule membranes are highly enriched in the purine oxidizing enzyme xanthine oxidoreductase (XOR). Transport of milk components Pathway III depicts transcytotic pathways for transport of proteins and other macromolecules. Transcytotic secretion of immunoglobulin A in rabbit mammary glands has been shown to occur. Prolactin and transferrin transcytosis have been detected Transfer of labeled low-density lipoprotein (LDL) from blood to milk has been reported. Considering that xenobiotic agents, including carcinogens and some drugs, can bind to and be transported by lipoproteins. Transport of milk components Pathway IV depicts transport of: monovalent and polyvalent ions glucose amino acids Transport of milk components Ion transport: Transporters or channels for sodium, potassium and chloride have been identified on the basal and apical plasma membranes of alveolar cells. Phosphate and iodide transporters appear to be limited to the basal membrane. Transport of milk components Glucose transport: Glucose transport systems have been detected in the mammary gland at both the apical and basal plasma membrane, and on Golgi and secretory vesicle membranes. Two distinct glucose transport mechanisms have been identified in the mammary gland: GLUT1 transporter mechanism A sodium dependent glucose transporter Transport of milk components Amino acid transport: Both sodium-dependent and sodium independent amino acid transport mechanisms analogous to those found in other organs have been demonstrated at the basolateral component of the mammary epithelium. Other agents: The presence of higher than expected concentrations of certain drugs in milk have raised the possibility that alveolar cells may have active transport mechanisms for such compounds. Transport of milk components Pathway V depicts transport the paracellular pathway for direct, bi-directional, extracellular movement of both low-molecular-weight substances and macromolecular solutes. This pathway is closed during lactation in humans and most other species by the presence of very tight-junction. Milk fat depression (MFD) Several theories have been proposed to explain the physiology behind this reduction in fat synthesis. Lower production of acetic and butyric acids in the rumen caused less fat production in mammary gland. The greater proportionate production in rumen increases the blood insulin, which partitions nutrients away from the mammary gland. A more current theory is that the combination of high grain and high unsaturated fatty acids in the diet causes the microorganisms in the rumen to produce more trans fatty acids. Milk fat depression (MFD) Avoiding milk fat depression Proper cooling of cows Control the amount of polyunsaturated fatty acids in the diet Balance dietary carbohydrates Buffer and alkalinizing agents Ionophores Feeding Management