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Invited Review: Bovine Milk Fat Globule Membrane as a Potential Nutraceutical

BioVita Technologies, Bat Yam, Israel

E-mail: vspits20{at}hotmail.com.

	ABSTRACT

TOP ABSTRACT INTRODUCTION ACKNOWLEDGEMENTS REFERENCES

 
For the last 15 yr, a great deal of knowledge has been accumulated on health beneficial factors, protein and nonprotein, of bovine milk fat globule membrane (MFGM). Among the health-beneficial components of the MFGM are cholesterolemia-lowering factor, inhibitors of cancer cell growth, vitamin binders, inhibitor of Helicobacter pylori, inhibitor of beta-glucuronidase of the intestinal Escherichia coli, xanthine oxidase as a bactericidal agent, butyrophilin as a possible suppressor of multiple sclerosis, and phospholipids as agents against colon cancer, gastrointestinal pathogens, Alzheimer’s disease, depression, and stress. All of the above compel us to consider bovine MFGM as a potential nutraceutical.

Key Words: bovine milk fat globule membrane • milk anticancer protein • phospholipid • cholesterolemia

Abbreviation key: BRCT = C-terminal domain of BRCA1 protein, BTN = butyrophilin, CHD = coronary heart disease, EAE = experimental autoimmune encephalomyelitis, FABP = fatty acid binding protein, MFGM = milk fat globule membrane, MOG = myelin oligodendrocyte glycoproteins.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION ACKNOWLEDGEMENTS REFERENCES

 
Milk fat in the lactating cow is secreted as myriads of lipid droplets of size 0.1 to 15 µm. These micro lipid droplets are encircled by a special membrane composed of lipid bilayer and proteins. This membrane has been designated the milk fat/lipid globule membrane (MFGM). The MFGM originates from the plasma membrane of the mammary gland secretory cells by extrusion of lipid droplet from the cell (Kanno, 1990; Mather and Keenan, 1998). Because each lipid droplet in milk has its own membrane envelope, i.e., the MFGM, the lipid droplets are present in milk in a dispersed form and, therefore, do not aggregate with each other. Only after destruction of the structure of the MFGM through, for example, a mechanical force like churning, do the lipid droplets aggregate and subsequently form large fat clumps known as butter. Milk fat globule membrane is composed of proteins and lipids in a 1:1 weight ratio (Kanno, 1990). Analysis of the protein entity of bovine MFGM by SDS-PAGE has demonstrated that MFGM has a large number of polypeptides, at least 50, ranging from 10 to 300 kDa (Spitsberg and Gorewit, 1998; Mather, 2000). A similar number of protein polypeptides can be seen in human MFGM (Goldfarb, 1997; Spitsberg and Gorewit, 1998). Many of these proteins are present in the MFGM as glycoproteins (Greenwalt et al., 1992; Mather, 2000). Table 1 lists some of the proteins identified in bovine MFGM. The main protein of the MFGM is the glycoprotein butyrophilin (about 40% of the total proteins of the MFGM), and the second representative protein of the MFGM is xanthine oxidase, which comprises 12 to 13% of the total. Other proteins are present in MFGM each at 5% or less. The physiological role of the MFGM proteins is not completely clear despite numerous research studies. However, there are some reasonable suggestions about the physiological function of these proteins in the cell because these proteins are an integral part of the plasma membrane of secretory mammary gland cell.

The bovine BRCA1 protein reveals 72.5% sequence identity with the human BRCA1 protein and conservation of amino acids involved in BRCA1 structure and function (Krum et al., 2003). It is noteworthy that, although the bovine C-terminus is truncated by 7 amino acids compared with the human protein, the bovine BRCA1 protein exhibits a similar cell cycle-regulated nuclear expression pattern. The C-terminal domain (BRCT) of the both BRCA1 proteins, human and bovine, has a similar activity in binding the phosphopeptides important in DNA damage responses (Krum et al., 2003; Rodriguez et al., 2003). One of the BRCT domain mutations, Met 1775Arg, which fails to bind phosphopeptides, relates to predisposition of women to breast and ovarian cancer (Manke et al., 2003). The BRCA2 protein, as well as the BRCA1 protein, is involved in DNA repair processes, although it has an additional function as one of the direct regulators of cytokinesis (Daniels et al., 2004). Our concept on the possible prevention of cancer using bovine MFGM as a food supplement is based on the suggestion that after the consumption of the MFGM, a certain number of inhibitory peptides will be released from the MFGM and subsequently will be absorbed in the digestive tract. The absorbed peptides could enter the bloodstream, and after reaching the organs or tissues, they could exert their inhibitory action on the cells undergoing carcinogenic transformation.

This concept has been inspired by the following facts: 1) a small peptide with 11 amino acid residues identical to the C-terminal of bovine mammary gland FABP was found to be a potent inhibitor of cell growth (Grosse and Langen, 1990; Spitsberg et al., 1995); 2) Japanese researchers (Adachi et al., 1993) demonstrated that the epidermal growth factor (molecular weight 5 to 6 kDa), given to rats orally with bovine MFGM, was subsequently detected in the portal vein; and 3) some success was achieved in the introduction of therapeutic peptides and proteins through the gastrointestinal tract (Banga, 1995).

It is important to note that in the last 10 to 15 yr, there have been several efforts to develop functional foods, including dairy foods. There is a trend to make functional dairy products by introducing into them a certain amount of biologically active peptides generated from milk proteins, to prevent the development of chronic diseases or cancer in humans (Kilara and Panyam, 2003). The concept of functional food is based on the suggested absorption of active peptides in the digestive tract.

The work on inhibition of the growth of experimental tumors by the BRCA1 peptides given orally to animals would be important to justify the application of bovine MFGM as a food supplement for preventing breast and ovarian cancer. We do not exclude the possibility that the above mentioned bovine homolog of human C-terminal BRCT domain, containing Met residue in a highly conserved 31-residue sequence (1756 to 1787), may substitute the mutated (1775 MetArg) human BRCA1 in harboring the phosphopeptides important in DNA damage response.

There is an interesting observation that bovine MFGM contains a component, likely of protein origin, which could inhibit in vitro the purified E. coli beta-glucuronidase (Ito et al., 1993), the enzyme involved in the intestinal degradation of glucuronides. The liver plays an essential role in detoxification of many metabolites of endogenous and exogenous origin. The enzyme glucuronyl transferase is important in such a detoxification. Glucuronyl transferase neutralizes the toxic compounds in liver cells through the formation of glucuronides, which are subsequently excreted. Some bacteria in the intestine have the enzyme beta-glucuronidase, which degrades the glucuronides with release of toxic agents, some of which might be carcinogenic, and stimulate the formation of, for example, colon cancer. Therefore, the consumption of MFGM could prevent colon cancer due to the presence of the inhibitor of beta-glucuronidase.

Beside the protein components of MFGM with potential anticancer effects, MFGM also contains an essential amount of phospholipids (Kanno, 1990), one of which, sphingomyelin, can exert anticarcinogenic activity. There is experimental evidence that dietary sphingomyelin suppresses colon carcinogenesis; sphingosine and ceramide have induced apoptosis in a human adenocarcinoma cell line, and feeding sphingolipids to Min (multiple intestinal neoplasia) mice has reduced the number of colon tumors and aberrant crypt foci (Vesper et al., 1999; Parodi, 2001; Berra et al., 2002; Hertervig et al., 2003; Lemonnier et al., 2003).

Anticholesterolemic Effects
Howard and Marks (1979) made an interesting observation on the content of serum cholesterol in a group of human volunteers fed a diet rich in butter and in another group fed cream containing an equal amount of fat. Serum cholesterol of the volunteers fed cream did not increase as much as that of the volunteers fed butter. This observation could be explained only by a substantial difference between the 2 diets. Milk fat globule membrane, as an essential component of cream, was suspected as the main factor in lowering the serum cholesterol level. Later, Ito et al. (1992) confirmed this suggestion. These researchers observed a direct inhibitory effect of bovine MFGM on hypercholesterolemia in the rat. This inhibition was explained by a significant binding of cholesterol by MFGM in the intestines of experimental animals. However, these authors did not exclude the influence on serum cholesterol by other substances of the MFGM such as, for example, phospholipids. Recently, Noh and Koo (2004) have demonstrated that one of the milk phospholipids, sphingomyelin, is an effective inhibitor of intestinal absorption of cholesterol in rats. The inhibition has been explained by a direct inhibiting effect of the highly saturated long chains of fatty acyl groups of milk sphingomyelin on the rate of luminal lipolysis, micellar solubilization, and transfer of micellar lipids to the enterocyte.

Effect on Helicobacter pylori Infection
It has been noted that some forms of stomach diseases such as chronic type B gastritis, peptic ulcer disease, and stomach cancer can etiologically be attributed to the colonization of stomach mucosa with Helicobacter pylori (Cover and Blaser, 1992; Ernst, 1999). Helicobacter pylori can cause in vitro hemagglutination, and this sialic acid-specific process can be inhibited by sialyated glycoproteins, including milk glycoproteins (Hirmo et al., 1998). This observation stimulated further investigation of H. pylori infection of the stomach mucosa. Wang et al. (2001) demonstrated that glycoproteins of bovine MFGM were capable of inhibiting the infection of H. pylori in a BALB/cA mouse model, and the hemagglutination and adhesion of H. pylori in HeLa S3 monolayers. In these experiments, MFGM was obtained from bovine buttermilk through a diafiltration process and defatted by extraction with chloroform-methanol. Both preparations of the MFGM, non-defatted and defatted, given orally (400 mg/kg of BW), caused equal healing effect on H. pylori infection of gastric mucosa in BALB/cA mice, which led to the conclusion that the major role in inhibition of H. pylori infection is played by the protein component of MFGM.

Effect of Butyrophilin on Autoimmune Encephalomyelitis
As indicated above, one of the main proteins of bovine MFGM is a glycoprotein with relative molecular weight of 66 to 67 kDa, named butyrophilin (BTN) (Franke et al., 1981). Butyrophilin is a mosaic protein, composed of functionally different peptide domains, and it spans the membrane. The exoplasmic N-terminal domain belongs to the Ig superfamily, and the cytoplasmic C-terminal domain (170 amino acid residues) belongs to B30.2 or rfp domain (Mather, 2000). The B30.2 domain is highly conserved and it can be found in 20 different proteins (Mather, 2000).

Recently, it has been reported that BTN can modulate the encephalitogenic T-cell response to myelin oligodendrocyte glycoprotein (MOG) in experimental autoimmune encephalomyelitis (EAE) related to human multiple sclerosis (Stefferl et al., 2000; Guggenmos et al., 2004). This property of BTN has been explained by the presence in its macromolecule of the extracellular IgV-like domain conserved in MOG and by cross-reactivity with the MOG peptide sequence 76–87. Butyrophilin can trigger the development of experimental EAE, or suppress disease. Mana et al. (2004) demonstrated that treatment of C57BL/6 mice with BTN either before or after immunization with MOG prevents or suppresses the clinical manifestation of EAE. These findings indicate that the consumption of dairy products enriched with MFGM can modulate the pathogenic response to MOG in a positive direction.

Effect of Phospholipids
We propose that the consumption of the MFGM alone as a nutraceutical or as a dairy food, or the consumption of food products enforced by the MFGM has health benefits due to the presence of phospholipids in the MFGM. Phospholipids of bovine MFGM constitute almost 30% of the total MFGM lipids. The 3 main MFGM phospholipids are sphingomyelin, phosphatidyl choline, and phosphatidyl ethanolamine. They comprise (weight %) 19.2 to 23.0, 25.7 to 41.1, and 27.0 to 35.0% of total MFGM phospholipids, respectively (Keenan et al., 1977; Kanno, 1990). Currently, it is considered that phospholipids, including milk-derived, affect numerous cell functions including growth and development, molecular transport systems, absorption processes, memory, stress responses, development of Alzheimer’s disease, and myelination in the central nervous system (Astaire et al., 2003; McDaniel et al., 2003; Oshida et al., 2003; Horrocks and Farooqui, 2004). Phospholipids also affect the development of colon cancer as discussed above.

MFGM as a Delivery System
Milk fat globule membrane can also serve as a putative delivery system for microelements such as Se (anticancer agent), fat-soluble vitamins, organic phosphates (see Table 2), and drugs (Sato et al., 1994).

MFGM and Coronary Heart Disease
There are contradictory observations regarding the effect of consumption of milk or dairy products on the development of coronary heart disease (CHD). Based on epidemiological analysis, Moss and Freed (2003) found that certified death rates from CHD positively correlated country-by-country with milk consumption. They suggested that CHD death could be associated with the nonfat portion of milk, namely, with the MFGM. This suggestion was based exclusively on the finding that the antibody against bovine MFGM circulating in human blood was bound to the fat globules of cow milk but not to those of human milk.

Because the study by Moss and Freed (2003) became one of the arguments to consider bovine MFGM as a component of milk deleterious to the human health (Riccio, 2004), it is necessary to scrutinize the results of the immunological experiments conducted in that study. They determined that the fluorescent-labeled antibody, prepared from the serum of a volunteer (CHD status unknown) against bovine MFGM, could bind to human platelets, large granular lymphocytes, and bovine MFGM, but not to human MFGM, yet a faint crescent of antibody was found trapped under the edge of one human milk fat globule (Moss and Freed, 2003). Although the authors did not indicate which MFGM proteins were recognized by the prepared antibody, the binding of the antibody to human platelets and to bovine MFGM strongly suggests that human platelets and bovine MFGM had a common antigenic site. It is most likely to be the well-known glycoprotein, CD36. This glycoprotein has been identified in the mammary gland, MFGM, platelets, and lymphocytes in humans and other mammals (Greenwalt et al., 1992; Macardle et al., 1996; Tassone et al., 1998). Glycoprotein CD36 is characterized by a highly conserved primary structure (Greenwalt et al., 1992). Given this, it is quite surprising that Moss and Freed (2003) were not able to detect the definite binding of the antibody to human MFGM. Overall, the suggestion made by Moss and Freed (2003) about the association of CHD with bovine nonfat milk component (MFGM) should be taken with caution.

A recent epidemiological study conducted in Sweden (Warensjo et al., 2004) reached the conclusion that the estimated intake of milk fat was not associated with cardiovascular risk factors or with increased risk of a first acute myocardial infarction.

	ACKNOWLEDGEMENTS

TOP ABSTRACT INTRODUCTION ACKNOWLEDGEMENTS REFERENCES

 
The author thanks Natalia Krasnova-Spitsberg for help in preparing the manuscript.

Received for publication November 20, 2004. Accepted for publication March 22, 2005.

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TOP ABSTRACT INTRODUCTION ACKNOWLEDGEMENTS REFERENCES

 


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