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Department of Animal Sciences
The Robert H. Smith Faculty
of Agricultural, Food & Environment

The Hebrew University of Jerusalem.

P.O. Box 12, Rehovot 76100, Israel
Phone: +972-(0)8-9489119;
Fax: +972-(0)8-9465763;
Yael Lewitus, Department's Secretary
e-mail: yaellew@savion.huji.ac.il

Publications

2019
Komsky-Elbaz, A. ; Saktsier, M. ; Biran, D. ; Argov-Argaman, N. ; Azaizeh, H. ; Landau, Y. S. ; Roth, Z. Atrazine-induced toxicity in goat spermatozoa is alleviated to some extent by polyphenol-enriched feed. Chemosphere 2019, 236. Publisher's VersionAbstract
Atrazine (ATZ) is one of the most extensively used herbicides to control growth of broadleaf and grassy weeds in crops. ATZ and its metabolites have deleterious effect on sperm quality. ATZ is also known for its ability to induce oxidative stress. Pistacia lentiscus (PL) is an evergreen shrub, with a high content of polyphenols in leaf extracts, with a known anti-inflammatory and antioxidant properties. The protective effect of PL or its extracts against ATZ-induced damage have not been yet evaluated. We examined the harmful effects of atrazine (ATZ) exposure on male reproductive system, using goat (Capra hircus) model spermatozoa and the protective effects of PL and PL ethanolic extract (PLE). In in-vivo experiments, male goats were fed a standard ration or one supplemented with 15 mg ATZ/kg body weight daily, for 6 months. Exposure to ATZ impaired the spermatozoa's morphology, viability, mitochondrial membrane potential and cell lipid composition. These alterations may in turn lead to reduced fertilization competence of the exposed spermatozoa. In an ex-vivo experiment, spermatozoa from male goats fed a standard ration or one supplemented with PL or PLE for 90 days and then were exposed to 1 μM ATZ or 10 μM of its major metabolite diaminochlorotriazine (DACT) through in-vitro capacitation. Prefeeding with PL or PLE partially attenuated the harmful effects of ATZ and DACT. Dietary supplementation with polyphenol-enriched feed can protect, to a certain extent, spermatozoa in males exposed to environmental toxicants. © 2019 Elsevier Ltd
German, J. B. ; Argov-Argaman, N. ; Boyd, B. J. Milk Lipids: A Complex Nutrient Delivery System. Nestlé Nutr Inst Workshop Ser, 2019, 90, 217 - 225. Publisher's VersionAbstract
The evolution of lactation and the composition, structures, and functions of milk's biopolymers illustrates that the Darwinian pressure on lactation selected for gene products with considerable structural complexity and diverse functions within the digestive system. For example, complex sugar polymers - oligosaccharides - possess unique properties in guiding the growth of intestinal bacteria that are not possible by feeding their simple sugars. The proteins of milk are diverse with some exhibiting enzymatic activities towards other milk components rendering those components both more digestible but also releasing biologically active products. Thus, research into milk's biopolymers has been most enlightening when milk was investigated for the formation and disassembly of its structures and for the functions within the infant. To date however, the most complex structure in mammalian milk, the fat globule, has not been effectively examined beyond its simple composition. The globules of milk are heterogeneous in size, composition, and function. With new research tools, scientists are beginning to understand the mechanisms that control the assembly of globules in the mammary gland and the disassembly within the infant.
Mesilati-Stahy, R. ; Argov-Argaman, N. Changes in lipid droplets morphometric features in mammary epithelial cells upon exposure to non-esterified free fatty acids compared with VLDL. PLOS ONE 2019, 13, e0209565 -. Publisher's VersionAbstract
The effects of the macrostructure of long chain fatty acids on the lipid metabolism and biosynthesis of lipid droplets (LD) was studied in mammary epithelial cells (MEC). MEC were exposed to similar compositions and concentrations of fatty acids in the form of either triglycerides (Tg), as part of the very-low-density lipids (VLDL) isolated from lactating cow plasma, or as non-esterified- free fatty acids (FFA). Exposing MEC to FFA resulted in two distinct processes; each independently could increase LD size: an elevation in Tg production and alterations in phospholipid (PL) composition. In particular, the lower PC/PE ratio in the FFA treatment indicated membrane destabilization, which was concomitant with the biosynthesis of larger LD. In addition, 6 fold increase in the cellular concentration of the exogenously added linoleic acid (C18:2) was found in MEC treated with FFA, implying that long chain fatty acids administrated as FFA have higher availability to MEC, enabling greater PL synthesis, more material for the LD envelope, thereby enhancing LD formation. Availability of long chain fatty acids administrated as VLDL-Tg, is dependent on LPL which its activity can be inhibited by the hydrolysis products. Therefore, we used increasing concentrations of albumin, to reduce the allosteric inhibition on LPL by the hydrolysis products. Indeed, a combined treatment of VLDL and albumin, increased LD size and number, similar to the phenotype found in the FFA treatment. These results reveal the role played by the macrostructure of long chain fatty acids in the regulation of LD size in MEC which determine the size of the secreted MFG.
Argov-Argaman, N. Symposium review: Milk fat globule size: Practical implications and metabolic regulation. Journal of Dairy Science 2019, 102, 2783 - 2795. Publisher's VersionAbstract
ABSTRACTMilk fat globule (MFG) size ranges over 3 orders of magnitude, from less than 200 nm to over 15 µm. The significance of MFG size derives from its tight association with its lipidome and proteome. More specifically, small MFG have relatively higher content of membrane compared with large globules, and this membrane exerts diverse positive health effects, as reported in human and animal studies. In addition, MFG size has industrial significance, as it affects the physicochemical and sensory characteristics of dairy products. Studies on the size regulation of MFG are scarce, mainly because various confounders indirectly affect MFG size. Because MFG size is determined before and during its secretion from mammary epithelial cells, studies on the size regulation of its precursors, the intracellular lipid droplets (LD), have been used as a proxy for understanding the mechanisms controlling MFG size. In this review, we provide evidence for 2 distinct mechanisms regulating LD size in mammary epithelial cells: co-regulation of fat content and triglyceride-synthesis capacity of the cells, and fusion between LD. The latter is controlled by the membrane's polar lipid composition and involves mitochondrial enzymes. Accordingly, this review also discusses MFG size regulation in the in vivo metabolic context, as MFG morphometric features are often modulated under conditions that involve animals' altered energy status.
2018
Mesilati-Stahy, R. ; Argov-Argaman, N. Changes in lipid droplets morphometric features in mammary epithelial cells upon exposure to non-esterified free fatty acids compared with VLDL. PLoS ONE 2018, 13. Publisher's VersionAbstract
The effects of the macrostructure of long chain fatty acids on the lipid metabolism and biosynthesis of lipid droplets (LD) was studied in mammary epithelial cells (MEC). MEC were exposed to similar compositions and concentrations of fatty acids in the form of either triglycerides (Tg), as part of the very-low-density lipids (VLDL) isolated from lactating cow plasma, or as non-esterified- free fatty acids (FFA). Exposing MEC to FFA resulted in two distinct processes; each independently could increase LD size: an elevation in Tg production and alterations in phospholipid (PL) composition. In particular, the lower PC/PE ratio in the FFA treatment indicated membrane destabilization, which was concomitant with the biosynthesis of larger LD. In addition, 6 fold increase in the cellular concentration of the exogenously added linoleic acid (C18:2) was found in MEC treated with FFA, implying that long chain fatty acids administrated as FFA have higher availability to MEC, enabling greater PL synthesis, more material for the LD envelope, thereby enhancing LD formation. Availability of long chain fatty acids administrated as VLDL-Tg, is dependent on LPL which its activity can be inhibited by the hydrolysis products. Therefore, we used increasing concentrations of albumin, to reduce the allosteric inhibition on LPL by the hydrolysis products. Indeed, a combined treatment of VLDL and albumin, increased LD size and number, similar to the phenotype found in the FFA treatment. These results reveal the role played by the macrostructure of long chain fatty acids in the regulation of LD size in MEC which determine the size of the secreted MFG. © 2018 Mesilati-Stahy, Argov-Argaman. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Scoble, J. A. ; Smilowitz, J. T. ; Argov-Argaman, N. ; German, B. J. ; Underwood, M. A. Plasma Lipoprotein Particle Subclasses in Preterm Infants. Am J Perinatol 2018, 35, 369-379.Abstract
OBJECTIVE:  A pilot study to determine lipoprotein classes and subclasses in premature infants and examine associations with nutritional intake, gestational age (GA), and morbidity. STUDY DESIGN:  Plasma lipoprotein particle concentrations were analyzed in a cohort of 15 premature infants in the first 5 days of life and again at 2 weeks. Breast milk samples were analyzed for fatty acid content. Associations between lipoprotein particle subclasses and GA, breast milk intake, milk fatty acid intake, and chronic lung disease (CLD) were determined. RESULTS:  At 2 weeks of age, more premature infants had higher concentrations of total very low-density lipoprotein and lower concentrations of total high-density lipoprotein (HDL) and large HDL particles (similar to profiles seen in adults and children with infectious disease, cardiometabolic disease, and diabetes). Lower total HDL, large HDL, and medium HDL and a higher small HDL:total HDL ratio at 2 weeks were each associated with CLD with GA a likely confounder. Intake of human milk C18 and C20 fatty acids was inversely correlated with plasma total LDL concentration at 2 weeks of age. CONCLUSION:  Dyslipidemia was common in extremely premature infants and was associated with CLD and with lower intake of specific long chain fatty acids.
2017
Argov-Argaman, N. ; Mandel, D. ; Lubetzky, R. ; Kedem, M. H. ; Cohen, B. - C. ; Berkovitz, Z. ; Reifen, R. Human milk fatty acids composition is affected by maternal age. The Journal of Maternal-Fetal & Neonatal Medicine 2017, 30, 34-37. Publisher's VersionAbstract
AbstractHuman colostrums and transition milk were collected from women under the age of 37 years and women aged 37 years and older. Transition milk of the younger group had lower fat content and 10-fold higher concentrations of omega 6 FA, eicosadecanoic, and arachdonic acids. Gestational age affected the colostrum concentration of total fat and omega 3 and omega 6 FA composition only in the older group. We concluded that age may be a factor in the FA composition of human milk. This should be taken into account when planning diets for pregnant women of different ages.
Shefer-Weinberg, D. ; Sasson, S. ; Schwartz, B. ; Argov-Argaman, N. ; Tirosh, O. Deleterious effect of n-3 polyunsaturated fatty acids in non-alcoholic steatohepatitis in the fat-1 mouse model. Clinical Nutrition Experimental 2017, 12, 37 - 49. Publisher's VersionAbstract
Summary Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathologies, ranging from hepatocellular steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. It has been suggested that fish oil containing n-3 polyunsaturated fatty acids (n-3 PUFA) induce beneficial effects in NAFLD. However, n-3 PUFA are sensitive to peroxidation that generate free radicals and reactive aldehydes. We aimed at determining whether changing the tissue ratio of n-3 to n-6 PUFA may be beneficial or alternatively harmful to the etiology of NAFLD. The transgenic Fat-1 mouse model was used to determine whether n-3 PUFA positively or negatively affect the development of NAFLD. fat-1mice express the fat-1 gene of Caenorhabditis elegans, which encodes an n-3 fatty-acid desaturase that converts n-6 to n-3 fatty acids. Wild-type C57BL/6 mice served as the control group. Both groups of mice were fed methionine and choline deficient (MCD) diet, which induces NASH within 4 weeks. The study shows that NASH developed faster and was more severe in mice from the fat-1 group when compared to control C57BL/6 mice. This was due to enhanced lipid peroxidation of PUFA in the liver of the fat-1 mice as compared to the control group. Results of our mice study suggest that supplementing the diet of individuals who develop or have fatty livers with n-3 PUFA should be carefully considered and if recommended adequate antioxidants should be added to the diet in order to reduce such risk.
Chertok, I. R. A. ; Haile, Z. T. ; Eventov-Friedman, S. ; Silanikove, N. ; Argov-Argaman, N. Influence of gestational diabetes mellitus on fatty acid concentrations in human colostrum. Nutrition 2017, 36, 17 - 21. Publisher's VersionAbstract
Objective The aim of this study was to examine differences in fatty acid concentrations in colostrum of women with and without gestational diabetes mellitus (GDM). The effect of GDM on fatty acid composition of colostrum is not fully understood, although rates of GDM are increasing globally. Methods A prospective case–control study was conducted of postpartum women with and without GDM. Gas chromatographic analysis was conducted to examine differences in colostral fatty acids of the colostrum samples of 29 women with and 34 without GDM. Results Analyses of the fatty acid composition revealed significantly higher concentrations of four essential ω-6 polyunsaturated fatty acids—γ-linolenic, eicosatrienoic, arachidonic, and docosatetraenoic—in the colostrum of GDM women compared with non-GDM women. Timing of collection influenced saturated medium chain fatty acid and monounsaturated fatty acid levels. Conclusions Differences in concentrations of ω-6 fatty acids but not in dietary linoleic fatty acid or ω-3 fatty acids suggest that altered concentrations are attributed to changes in specific endogenous metabolic pathways. Implications of higher concentrations of ω-6 fatty acids in the colostrum of women with GDM have yet to be determined. Timing of colostrum collection is critical in determining colostral fatty acid and metabolite concentrations.
Hadaya, O. ; Landau, S. Y. ; Glasser, T. ; Muklada, H. ; Dvash, L. ; Mesilati-Stahy, R. ; Argov-Argaman, N. Milk composition in Damascus, Mamber and F1 Alpine crossbred goats under grazing or confinement management. Small Ruminant Research 2017, 153, 31 - 40. Publisher's VersionAbstract
The interactive effect of breed and feeding management on milk composition was established in local goats (Damascus, Mamber) and their F1 Alpine crossbreeds, half of which grazed daily for 4h in Mediterranean brushland (Pasture – P) and half were fed clover hay (Hay – H) indoors, in addition to concentrate fed individually. Milk composition and fatty acid profile were measured, and individual nutritional composition was estimated by fecal NIRS; DM intake was calculated from the proportion of dietary concentrate. Milk and feces were collected at 65 (pretreatment), 110, 135 and 170 days of lactation. DM intake was lower in the H vs. P group (P<0.0001) in Damascus and Damascus crossbreed (P<0.01), but not in the other breeds. The Alpine crossbreeds yielded 0.6kg more milk (P<0.001) than their local counterparts. P group yielded milk that was richer in protein (P<0.01) and fat (P<0.0001), especially in the Damascus breed. Urea concentration in milk was 66% higher in H-group of all breeds throughout the experiment (P<0.001). H goats produced milk richer in medium-chain fatty acids (P<0.001) and monounsaturated fatty acids (P<0.01) than P goats. Omega 6 was higher for P goats with a strong breed×diet interaction effect (P<0.01) in Mamber goats. The P group produced milk that was 20% richer in omega 3 than the H group (P<0.0001). In the P group of Damascus goats, low omega 6/3 ratio was found compared with H group. This study shows that breed and management interact to affect milk composition and fatty acid profile. Therefore both factors and their interaction should be considered when industry pursues means to enrich milk with bioactive, essential lipid components which can turn milk into health promoting commodity.
Cohen, B. - C. ; Raz, C. ; Shamay, A. ; Argov-Argaman, N. Lipid Droplet Fusion in Mammary Epithelial Cells is Regulated by Phosphatidylethanolamine Metabolism. J Mammary Gland Biol Neoplasia 2017, 22, 235-249.Abstract
Mammary epithelial cells (MEC) secrete fat in the form of milk fat globules (MFG) which are found in milk in diverse sizes. MFG originate from intracellular lipid droplets, and the mechanism underlying their size regulation is still elusive. Two main mechanisms have been suggested to control lipid droplet size. The first is a well-documented pathway, which involves regulation of cellular triglyceride content. The second is the fusion pathway, which is less-documented, especially in mammalian cells, and its importance in the regulation of droplet size is still unclear. Using biochemical and molecular inhibitors, we provide evidence that in MEC, lipid droplet size is determined by fusion, independent of cellular triglyceride content. The extent of fusion is determined by the cell membrane's phospholipid composition. In particular, increasing phosphatidylethanolamine (PE) content enhances fusion between lipid droplets and hence increases lipid droplet size. We further identified the underlying biochemical mechanism that controls this content as the mitochondrial enzyme phosphatidylserine decarboxylase; siRNA knockdown of this enzyme reduced the number of large lipid droplets threefold. Further, inhibition of phosphatidylserine transfer to the mitochondria, where its conversion to PE occurs, diminished the large lipid droplet phenotype in these cells. These results reveal, for the first time to our knowledge in mammalian cells and specifically in mammary epithelium, the missing biochemical link between the metabolism of cellular complex lipids and lipid-droplet fusion, which ultimately defines lipid droplet size.
2016
Lu, J. ; Argov-Argaman, N. ; Anggrek, J. ; Boeren, S. ; van Hooijdonk, T. ; Vervoort, J. ; Hettinga, K. A. The protein and lipid composition of the membrane of milk fat globules depends on their size. 2016, 99, 4726 - 4738. Publisher's VersionAbstract
In bovine milk, fat globules (MFG) have a heterogeneous size distribution with diameters ranging from 0.1 to 15 µm. Although efforts have been made to explain differences in lipid composition, little is known about the protein composition of MFG membranes (MFGM) in different sizes of MFG. In this study, protein and lipid analyses were combined to study MFG formation and secretion. Two different sized MFG fractions (7.6±0.9 µm and 3.3±1.2 µm) were obtained by centrifugation. The protein composition of MFGM in the large and small MFG fractions was compared using mass-spectrometry-based proteomics techniques. The lipid composition and fatty acid composition of MFG was determined using HPLC-evaporative light-scattering detector and gas chromatography, respectively. Two frequently studied proteins in lipid droplet biogenesis, perilipin-2 and TIP47, were increased in the large and small MFG fractions, respectively. In the large MFG fraction, besides perilipin-2, cytoplasmic vesicle proteins (heat shock proteins, 14–3-3 proteins, and Rabs), microfilaments and intermediate filament-related proteins (actin and vimentin), host defense proteins (cathelicidins), and phosphatidylinositol were higher in concentration. On the other hand, cholesterol synthesis enzymes [lanosterol synthase and sterol-4-α-carboxylate 3-dehydrogenase (decarboxylating)], cholesterol, unsaturated fatty acids, and phosphatidylethanolamine were, besides TIP47, higher in concentration in the small MFG fraction. These results suggest that vesicle proteins, microfilaments and intermediate filaments, cholesterol, and specific phospholipids play an important role in lipid droplet growth, secretion, or both. The observations from this study clearly demonstrated the difference in protein and lipid composition between small and large MFG fractions. Studying the role of these components in more detail in future experiments may lead to a better understanding of fat globule formation and secretion.
Argov-Argaman, N. ; Hadaya, O. ; Glasser, T. ; Muklada, H. ; Dvash, L. ; Mesilati-Stahy, R. ; Landau, S. Y. Milk fat globule size, phospholipid contents and composition of milk from purebred and Alpine-crossbred Mid-Eastern goats under confinement or grazing condition. IDF International Symposium on Sheep, Goat and other non-Cow Milk 2016, 58, 2 - 8. Publisher's VersionAbstract
Milk fat globule (MFG) size and phospholipids (PL) content and composition were determined in milk collected at 65 (pretreatment), 110, 135 and 170 days of lactation from goats randomly assigned to grazing in Mediterranean brushland or fed clover hay indoors, in addition to concentrate. Daily feed intake and dietary contents of neutral detergent fibre and acid detergent fibre were higher in grazing goats, associated with milk richer in fat, with larger MFGs and 20% higher PL content. Smaller MFGs, produced by all confinement groups, was associated with 15 μg g−1 fat higher milk PL content. The greatest effect was found in the Damascus goats, with over 44% higher PL concentration, on milk fat basis, in the confined compared with grazing group. Our understanding of how PL content is modulated by the interaction between genetic background and nutrition will enable to achieve either PL-rich milk or PL-enriched milk fat.
Lubetzky, R. ; Argov-Argaman, N. ; Mimouni, F. B. ; Armoni Domany, K. ; Shiff, Y. ; Berkovitz, Z. ; Reifen, R. ; Mandel, D. Fatty acids composition of human milk fed to small for gestational age infants. The Journal of Maternal-Fetal & Neonatal MedicineThe Journal of Maternal-Fetal & Neonatal Medicine 2016, 29, 3041 - 3044. Publisher's Version