Endogenous fatty acid metabolism in the mammary gland

Endogenous FA metabolism in the mammary gland include de novo synthesis of short and medium-chain FA, desaturation and, to a limited extent, chain elongation of FA with two carbon atoms. The current section is limited to general principles and some recent findings on endogenous milk fatty acid synthesis that enhances human health (particularly UFA) and allows to monitor animal health (odd- and branched-chain fatty acids and trans fatty acids). As major mammary lipogenic pathways seem to differ between species it is worth mentioning that these are bovine results; for example, the abundance of mRNA encoding for genes involved in lipid metabolism, as well as enzyme activities related to fatty acid and lipid synthesis in the mammary gland of the caprine and the bovine, shows strong species specificities (Bernard et al., 2017).

Endogenous mammary metabolism of odd and branched-chain fatty acids

The de novo synthesis of FA in the mammary gland is mainly catalyzed by FA synthase (FASN)and acetyl-CoA carboxylase (ACACA). In this process, malonyl- CoA, generated from acetyl-CoA, is the elongation substrate used to produce short and medium even-chain FA with acetyl-CoA as a primer. Replacing acetyl- CoA by propionyl-CoA as a precursor in this process explains the occurrence in milk of (trace amounts of) 5:0, 7:0, 9:0, 11:0 and 13:0, although traces of the latter FA are also detected in duodenal contents (Dodds et al„ 1981; Massart-Leen et al., 1983). Moreover, ruminal infusion of propionate increased the amount of not only the former odd-chain FA in milk fat, but also 15:0 and 17:0 (Rigout et al., 2003; Maxin et al., 2011; French et al., 2012). As such, this process adds to 15:0 and 17:0 transferred from the duodenum, similar to the dual origin of 16:0 in milk fat. Where de novo synthesis in the mammary gland has been suggested to contribute to about half of the secretion in milk of 16:0, this process also has been suggested to contribute to at least one-third of the 15:0 and 17:0 secretions in milk (Vlaeminck et al., 2015).

On the other hand, mammary FASN does not seem to elongate isovaleryl- CoA, 2-methylbutyryl-CoA and isobutyryl-CoA to iso odd chain, anteiso odd chain or iso even chain FA, as suggested from infusion studies with (labelled) isovalerate (Verbeke et al., 1959; French et al., 2012) and 2-methyl butyrate

(French et al., 2012). Nevertheless, recoveries above 1.0 were observed for iso 17:0 (e.g. Dewhurst et al., 2007) and anteiso 17:0 (e.g. Vlaeminck et al., 2006). Although FA elongation with two carbon atoms to generate FA beyond 16 carbons does not seem relevant in milk FA synthesis of linear even and odd chain FA, Vlaeminck et al. (2015) provided evidence of a post-ruminal 2-carbon elongation of contributing to the secretion of iso 17:0 and anteiso 17:0. Flowever, the partial conversion of iso 15:0 and anteiso 15:0 to their C17 counterparts also seems to occur prior to the mammary gland (e.g. in duodenal epithelial cells), as suggested from the enrichment of iso 17:0 and anteiso 17:0 in plasma TAG as compared to duodenal contents (Vlaeminck et al., 2015).

Finally, odd chain FA can further be metabolized by A9-desaturase activity, but only the conversion of 17:0 to 17:1 seems of quantitative importance (Fievez et al., 2003).

Endogenous mammary metabolism of saturated and mono-unsaturated fatty acids

Stearoyl-CoAdesaturase (SCD) is an important enzyme in the bovine mammary gland. It converts SFA into mono-unsaturated FA (MUFA) by introducing a double bond between carbon atoms 9 and 10 in the saturated carbon chain, for example, desaturation of 18:0 to cis-9 18:1 (Annison et al., 1967). However, it can also catalyze the desaturation of MUFA, particularly of trans-11 18:1 to generate cis-9, trans-11 CLA (Griinari et al., 2000).

4.2.1 Endogenous mammary metabolism of poly-unsaturated fatty acids

Fatty acid elongation with two carbon atoms to generate FA with chain lengths beyond 16 carbons is a very common process in various ruminant tissues, except for the mammary gland (Moore and Christie, 1981).

Impact of ruminant fatty acids on human health

According to a cohort study in 13 European countries, dairy products were estimated to contribute from 14% (Spain) to 40% (Germany) of the total dietary fat intake (Hulshof et al., 1999), indicating the significance of ruminant FA in the Western diet. The FA profile of ruminant animal products is mainly saturated, as biohydrogenation is extensive, resulting in 18:0 being the major FA leaving the rumen (Shingfield and Wallace, 2014). As 18:0 is a neutral FA regarding human health, biohydrogenation to 18:0 is neither negative nor positive for human health. However, the reduction of unsaturated 18-carbon FA to 18:0 in the rumen is incomplete and a series of 18:1, 18:2 and 18:3 intermediates accumulate with double bonds of different positions and configurations.

Among this plethora of UFA, some might positively or negatively impact human health depending on the FA structure.

Impact of ruminant trans fatty acids on human health

Under normal conditions, the major trans FA present in milk or dairy products is trans-11 18:1 (25-75% of total 18:1 isomers) (Lock and Bauman, 2004). According to Kuhntetal.(2006), 19-24% of dietary trans-1118:1 is endogenously converted to cis-9, trans-11 CLA in humans by A9-desaturase, and this CLA isomer has been shown to have anticarcinogenic and anti-atherogenic effects (Lock and Bauman, 2004). However, the remaining trans-11 18:1 which is not converted might increase cancer risk as suggested by human epidemiological studies (odds ratio ranging from 0.30 to 3.69; Field et al., 2009). Nevertheless, this is not supported by animal and in vitro studies which have been performed (Field et al., 2009). Furthermore, in human Tcells, trans-11 18:1 has been shown to have a cytokine reducing effect (interleukin-2 and tumor necrosis factor-a), which was independent of cis-9, trans-11 CLA as no bioconversion occurred (Jaudszus et al., 2012). This indicates that trans-11 18:1 might also have health- promoting effects beyond those associated with cis-9, trans-11 CLA (Field et al.,

2009). In their state-of-the-art summary, Kuhnt et al. (2016) summarized several human intervention studies related to ruminant trans FA, in which three- and ten-fold amounts of ruminant trans FA were compared to levels consumed by the average population. They concluded that with the average amounts ingested, no negative effects on human health were observed. The amount of ruminant trans FA that induced negative effects on blood lipids was extremely high and not realistic (11-12 g/day, for example, corresponding to a daily combined consumption of about 490 g cheese, 1200 mL milk, 430 g yoghurt and 80 g butter as calculated from data reported by Kuhnt et al., 2016).

When high-starch diets are fed to dairy cows, a shift might occur in milk- fat profile from mainly trans-11 18:1 towards increased proportions of trans-10 18:1 (e.g. Conte et al., 2018). Individual trans isomers of 18:1 might have specific properties (Ferlay et al., 2017). Epidemiological studies showed a negative impact of industrial trans FA on serum cholesterol and lipoprotein metabolism, thereby increasing the risk for coronary heart disease (Kuhnt et al., 2016). As such, since industrial fatty acids are particularly rich in trans-10 18:1, milk rich in trans-10 18:1 might have a negative effect on human health. Nevertheless, with trans-10 18:1 containing milk (products), no human intervention studies have been performed yet and only two animal studies compared trans-10 18:1 containing milk or butter with trans-11 18:1 containing milk or butter. Roy et al. (2007) observed increased total cholesterol and LDLcholesterol concentrations in plasma and increased lipid deposition in the aorta of rabbits supplemented with trans-10 18:1 compared to trans-11 18:1 enriched butter. Furthermore, in rats, treatment with trans-10 18:1-enriched milk fat tended to increase TAG concentration, whereas treatment with trans-11 18:1 and c/s-9, trans-11 CLA containing milk fat tended to reduce it (Anadon et al., 2010). Although those animal studies showed a potential negative risk of trans-10 18:1 containing milk (products) for human health, extrapolation of findings from animal studies to humans has to be made with caution.

Impact of conjugated linoleic acids and n-3 fatty acids on human health

A wide range of CLA isomers with double bond positions from 7 to 9 and from 12 to 14 in different combinations of geometrical configurations have been identified in dairy products, with cis-9, trans-11 CLA being the predominant isomer (-90%) (Ferlay et al., 2017). The health effects of CLA have been extensively studied, showing a variety of positive effects on health, such as anticarcinogenic, anti-obesity and anti-inflammatory effects (Dhiman et al., 2005; Ferlay et al., 2017). However, almost all studies were performed using a synthetic mixture of CLA isomers, containing equal amounts of the cis-9, trans- 11 and trans-10, c/s-12 isomer (80-95%) and other minor CLA isomers. Recently, a few studies showed beneficial effects of trans, trans CLA isomers (eithertrans- 9, trans-11 or a mix) on health, such as anticarcinogenic, anti-inflammatory, antiplatelet aggregation and hypocholesterolemia effects as well as prevention of fatty liver (Kim et al., 2016). Overall, CLA consumption has been shown to improve human health (Dhiman et al., 2005). Nevertheless, more research is needed to elucidate the metabolic role of individual CLA isomers and their interaction.

Considering PUFA, a differentiation is made between the n-3 and n-6 series of long-chain FA (LCFA), which are formed by elongation and desaturation of the essential linolenic (18:3n-3) and linoleic (18:2n-6) acids, respectively, and can be further converted to eicosanoids. n-6 eicosanoids, derived from arachidonic acid (20:4n-6, AA), are known to have pro-inflammatory properties, while n-3 eicosanoids, derived from EPA have an anti-inflammatory effect (Wall et al., 2010). As the formation of the n-3 and n-6 series of LCFA from its precursors are catalyzed by the same set of enzymes, competition exists. As a result, a low n-6 to n-3 ratio (between 1:1 and 4:1) is recommended (Wall et al.,

2010). In comparison, in Western diets (high in 18:3n-3), this ratio is estimated between 15:1 and 20:1 (Simopoulos, 2001). Even though dairy fat is highly saturated, a Dutch study estimated that milk fat contributes significantly to the intake of the essential n-3 PUFA 18:3n-3 (5.3-15.7%), but to a lesser extent to the intake of the essential n-6 PUFA 18:2n-6 (1.8 to 3.6%) (van Valenberg et al., 2013). Several very-long-chain n-3 and n-6 PUFA are consumed mainly via the intake of milk fat (van Valenberg et al., 2013), which shows an n-6 to

n-3 ratio of 2.28, within the desired range. The only very long-chain PUFA for which recommendations of intake have been formulated are EPA and DHA. The contribution of milk fat in the intake of DHA is marginal, while, in contrast to previous reports (Meyer et al., 2003; Sioen et al., 2006; Astorg et al., 2004), 10-15% of the daily EPA intake was estimated to originate from milk fat (van Valenberg et al., 2013).

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