Milk Lipid Regulation at the Maternal-Offspring Interface

Abstract

Milk lipids provide a large proportion of energy, nutrients, essential fatty acids, and signaling molecules for the newborns, the synthesis of which is a tightly controlled process. Dysregulated milk lipid production and composition may be detrimental to the growth, development, health and survival of the newborns. Many genetically modified animal models have contributed to our understanding of milk lipid regulation in the lactating mammary gland. In this review, we discuss recent advances in our knowledge of the mechanisms that control milk lipid biosynthesis and secretion during lactation, and how maternal genetic and dietary defects impact milk lipid composition and consequently offspring traits.

1. Introduction

1.1 Lactation

Lactation is a highly energy- and nutrient-demanding physiological process that is crucial for the normal development of the newborn mammals. Mother’s milk is the sole and ideal food for the newborn mammals before they are able to eat and digest solid food. It is widely regarded as nutritious and protective for the early postnatal development as it can provide not only nutrients but also immune-defensive factors [1–3]. Lipids are one of the main constituents of milk, which makes the lactating mammary gland one of the most active organs for lipid synthesis, transport and secretion in the body [4–7]. For example, the mammary glands of a lactating mouse synthesize and secrete approximate 32 g of milk lipids over a lactation period of 20 days, equivalent to its entire body weight [5]. In humans, a lactating mother can secrete nearly 6 kg of milk lipids during a typical six-month lactation period [4]. Thus, milk lipid is an important source of both calories and essential fatty acids for the newborns. In mice, nearly 80% of calories needed for development of the neonate is provided by milk lipids [7]. Although there are some differences in the compositions of milk from different species, the main regulatory mechanisms of milk synthesis and secretion are largely conserved [8].

1.2 Mammary Gland and Milk Lipid Synthesis and Secretion

Mammary gland is responsible for milk production during lactation, which is a very dynamic tissue continually undergoing changes in structure and function [9–11]. The development of mammary gland has been well characterized into five stages: embryogenesis, pubertal development, and development in pregnancy, lactation and involution [9, 10]. During the transition from pregnancy to lactation, the mammary glands undergo a complex set of development under the coordinated control of many hormonal, metabolic and secretary pathways [7, 12, 13], and finally the functional lactating mammary gland is composed of a branching network of ducts formed of epithelial cells ending in extensive lobulo-alveolar clusters that is ready for milk synthesis and secretion. Immediately after parturition, the activity of lipid biosynthetic enzymes increases rapidly in mammary gland resulting in secretion of milk with about 30% lipid [7, 14–16]. Milk lipid synthesis and secretion requires the coordination of multiple biochemical and cellular events in the mammary epithelial cell (MEC) [10, 17, 18]. Milk lipids in the form of milk fat globules (MFG) are produced in the milk-secreting cells called alveoli [12]. Up to 98% of milk lipids are triacylglycerides (TAGs) predominantly composed of short and medium chain (C8–C12) fatty acids (FAs) [8], thus a constant supply of FAs for TAG synthesis in lactating mammary gland is necessary. Overall, there are three types of substrate sources that can be utilized for synthesizing milk TAG: dietary fat, FAs mobilized from adipose tissue stores, and lipids synthesized from de novo synthesis [7, 8, 19, 20]. FA composition and secretion rate of milk TAG can vary depending on maternal genetics and environmental factors such dietary fat [8, 21, 22]. A network of genes that is involved in regulating mammary lipid synthesis and secretion has been revealed including a number of transcription factors such as sterol regulatory element-binding proteins (SREBPs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs) [13, 23]. To date, lactation defects in many transgenic (TG)/knockout (KO) mice have been analyzed, and some of them have been reviewed by McManaman and his colleagues [11]. These studies contribute greatly to our understanding of genetic control of mammary gland development and the regulation of milk lipid synthesis and secretion. These genes include but not limited to prolactin (PRL) or prolactin receptor (PRLR) [24, 25], oxytocin [26, 27], insulin-like growth factor 1 (IGF1) [28], diacylglycerol transferase 1 (DGAT1) [29, 30], tyrosine kinase Src [31], protein kinase N1 (PKN1) [32], xanthine oxidoreductase (XOR) [33, 34], butyrophilin subfamily 1 member a1 (BTN1A1) [35], cell death-inducing DNA fragmentation factor α-like effector A (CIDEA) [36], adipophilin (ADPH) [37–39], and microRNA-150 [40].

In this review, we will summarize the recent advances about the lipid regulation at the maternal-offspring interface during lactation. Specifically, we will focus on how maternal genetic modifications and dietary factors such as high-fat diet (HFD) affect milk lipid regulation, and their subsequent consequences on the offspring development. Several gene targets closely related to milk lipid regulation including SREBP-1, serine/threonine-specific protein kinase B (Akt/PKB), thyroid hormone responsive spot 14 (S14), PPARγ, very low-density lipoprotein receptor (VLDLR), and adiponectin are discussed.

2. Genetic Control of Milk Lipid Biosynthesis and Secretion during Lactation

2.1 SREBP-1

It has been well known that lipid synthesis in liver and adipose tissue is regulated by a family of membrane-bound transcription factors designated as SREBP-1 pathway [41–43]. SREBP-1 regulates the expression of many key genes necessary for fatty acid synthesis by binding to the sterol response element (SRE) in their promoters. The two isoforms, SREBP-1a and SREBP-1c, are generated from differential translation start sites in the SREBP-1 transcript [43]. SREBP-1a can activate genes in both cholesterol and FA synthesis pathways, and SREBP-1c primarily activates genes required for FA and TAG synthesis [42–44]. The mRNAs for SREBP-1a, SREBP-1c, and several downstream targets are upregulated dramatically in the mammary gland at the onset of lactation [23, 45], suggesting a possible role in milk lipid synthesis. SREBP-1c-null mice show only very minor deficiencies in lipid synthesis during lactation, possibly due to the compensatory upregulation of SREBP-1a expression [45]. To test this possibility, complete loss of SREBP-dependent genes was achieved by deletion of SREBP cleavage-activating protein (SCAP) specifically in the MECs [45]. SCAP is both an escort for SREBPs and a sensor of sterols [42, 44, 46]. Disruption of SCAP severely decreased pup growth rate, but the pups did not die [45]. Consistent with the reduced mRNA expression of fatty acid synthase (FASN), insulin-induced gene 1 (INSIG1), mitochondrial citrate transporter (SLC25A1), and stearoyl-CoA desaturase 2 (SCD2) in SCAP KO mice, the proportion of de novo synthesized FAs in the milk decreased by 25%, suggesting that SREBP-dependent pathway is necessary for optimal lipogenesis in the lactating mammary gland. An in vitro study found that overexpression of SREBP-1 promoted de novo FA synthesis and TAG accumulation in goat MECs [47], further confirming the role of SREBP-1 pathway in milk lipid synthesis. In addition, SREBP-1 is involved in the regulation of bovine mammary lipid synthesis during diet-induced milk fat depression [48]. It should be noted that FA synthesis in the mammary gland may differ from that in liver and adipose tissue, as mammary alveolar cells contain thioesterase II, a special enzyme that terminates FA synthesis after the addition of 8–16 carbons [49]. Saturated FAs with 6–14 carbons are the major product of de novo FA synthesis in lactating mammary gland [50]. Longer chain FAs in milk are shown to originate from the diet or from mobilization of adipose tissue TAGs [51]. Polymorphisms in genes in the SREBP-1 signaling pathway and SCD are associated with altered milk FA composition [52, 53]. SREBP-1c is a known target of LXRs; and the activation of SREBP-1c by LXRs is accompanied by an increase in FA synthesis [54–56]. LXRs are members of the nuclear hormone receptor (NHR) superfamily that are bound and activated by oxysterols. One study in bovine MECs showed that activation of LXRs can enhance de novo FA synthesis [57]. Another one in goat MECs suggested that LXRα promotes the synthesis of monounsaturated FAs via the control of SCD1 in an SREBP-1-dependent manner [58]. In summary, genes in the LXR-SREBP-1 pathway play an important role in the regulation of milk lipid synthesis.

2.2 Akt

We have already known that SREBP-1 is an important regulator of secretory activation with regard to lipid biosynthesis. Recently this process has been suggested to be influenced by Akt [59–61], which is known to be activated by a wide variety of stimuli and can mediate many cellular and physiological processes through phosphorylation of numerous substrates [62]. Akt is expressed during mammary gland development, and its expression is upregulated during pregnancy and lactation and is decreased at the onset of involution [5, 63]. The roles of Akt in regulating lactation process have been examined using mouse genetic models [5, 64, 65]. Overexpression of constitutively activated Akt in the mammary glands of Akt TG mice results in delayed involution and onset of apoptosis [64]. Further analysis shows that Akt overexpression also results in precocious lipid droplet formation in MECs, as well as excess lipid synthesis causing the secretion of milk with significantly higher lipid content [5], suggesting that Akt upregulation may help meet the increased lipid biosynthetic demand during pregnancy and lactation, but Akt must be downregulated in order for a timely mammary gland involution to occur. Consistent with these in vivo observations, in vitro result shows that overexpression of recombinant human active Akt in mammary epithelial cell line CIT3 leads to an increase in glucose transport and lipid biosynthesis, further confirming the role of Akt in the developmental regulation of milk lipid metabolism in lactating mammary gland [5]. Indeed, a lactation defect is observed in the Akt TG mice, because the body weight of the pups in the litter is decreased by 50% over the first 9 days of lactation. The retarded growth of pups nursed by TG mothers may result from the inability of the pups to acquire sufficient quantities of milk by suckling, possibly due to the high viscosity of the milk [5]. In addition, Akt may also contribute to the regulation of milk secretion by modifying the formation and accumulation of cytoplasmic lipid droplets in MECs [5]. In a later study, the question whether Akt and which Akt isoform is required for these processes is answered by Akt KO mouse model. The results show that loss of Akt-1 but not Akt-2 specifically causes defects in glucose uptake and lipid synthesis in the lactating mammary gland, which is severe enough to lead to growth defects and pup mortality due to the insufficient quantities of milk [65]. Further deletion of one allele of Akt-2 in Akt-1-KO mice results in a more severe lactation defect (i.e. decreased milk production) due to the loss of terminal differentiation in the mammary gland during late pregnancy [66]. Decreased lactation capacity is also observed in insulin receptor substrate (IRS) null mice, and this might be associated with reduced insulin-dependent phosphorylation of mammary Akt [60]. Overall all these studies highlight that Akt is required for lactating mice to synthesize and secret milk.

2.3 S14

S14 was first discovered in 1981 while screening rat hepatic proteins regulated by thyroid hormone [67]. S14 is highly expressed in lipogenic tissues including liver, adipose tissue and lactating mammary gland and associated with lipogenesis [68–71]. The roles of S14 in de novo lipogenesis have been reported as inhibition in liver and activation in lactating mammary gland, because S14 deletion increases hepatic de novo lipogenesis [72] but decreases the lipogenesis in lactating mammary gland [73]. The difference observed in these two tissues may be due to the coexpression of a paralogous S14 related gene (S14R or MIG12) in liver but not in lactating mammary gland as S14 and S14R can form heterodimers that are determined to be inhibitory in lipogenesis through reducing acetyl-CoA carboxylase (ACC) polymerization and activity [73–76]. The absence of S14R in lactating mammary gland facilitates researchers to elucidate the lipogenic roles of S14 in this tissue. Transcriptional analyses show that S14 mRNA is upregulated by about two-fold at the onset of lactation [23]. Deletion of S14 in the lactating mammary gland reduces de novo lipid synthesis, and the milk from S14-null mother shows a 33% reduction in TAG levels distinguished by lower levels of medium-chain fatty acids (MCFAs) [73, 77]. Similar to the findings from the SREBP-1 and Akt study, S14 KO mice show a lactation defect reflected by a retarded pup growth due to the reduced TAG content in milk. The lactation defect can be rescued by provision of a HFD to the lactating dam [77]. TG mice overexpressing S14 in MECs increase the amount of MCFAs without altering the total milk fat or influencing the growth of the offspring [77]. Further analysis shows that a molecular function of S14 in MECs is to enhance FASN catalysis during lactation when optimal milk MCFA production is needed [77]. S14 is also involved in milk fat production in dairy cows [48, 78]. Together, these findings support that S14 is required for the de novo lipid synthesis in the lactating mammary gland. Studies have suggested that S14 can be regulated at the transcriptional level by SREBP-1c, LXRs and other transcription factors involved in FA synthesis [45, 71, 79–81]. In addition, S14 expression is noted to be elevated in the mammary glands of Akt1 TG mice, which exhibit precocious lipid synthesis, suggesting the possible interaction between S14 and Akt in this process [23]. Considering the widespread contributions of S14 to obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) [71, 82], and the complex interactions of S14 with other factors, more studies will be required to address its function in the future.

3. Genetic and Dietary Regulation of Milk Composition and Neonatal Inflammation

Mother’s milk represents a unique metabolic entity that exerts direct consequences on the developing newborns, whose digestive and immune systems are still immature. Several studies in our lab have demonstrated that maternal genetic defects including PPARγ, VLDLR, and adiponectin, as well as maternal dietary defects such as high fat diet, can affect the composition of milk so that it triggers systemic inflammation and related disorders in the nursing offspring, which we have termed as “inflammatory milk” or “toxic milk” [83–87].

3.1 PPARγ

PPARγ is a member of a subfamily of the NRs that is known to promote adipogenesis and lipogenesis [88, 89]. It is also a well-known target with great specificity for PPAR agonist thiazolidinediones (TZDs), a class of drugs for the treatment of insulin resistance and type II diabetes [90]. In addition, it modulates lipid homeostasis and inflammatory responses [91–97]. The roles of PPARγ signaling in milk lipid metabolism have been revealed in several studies [98, 99], as many genes involved in milk lipid synthesis and secretion in ruminants MECs are regulated by PPARγ. Furthermore, trans-10, cis 12-conjugated linoleic acid-induced milk fat depression is associated with inhibition of PPARγ signaling and inflammation in murine mammary gland [100]. Germline deletion of PPARγ in mice leads to embryonic lethality [101]. Conditional KO of PPARγ specifically in hematopoietic and endothelial cells using Tie2cre mice results in increased lipid accumulation and elevated expression of lipid oxidation enzymes including 12-lipoxygenase (12-LO) and microsomal epoxide hydrolase (EPHX1) in the lactating mammary gland [83]. Consequently, the milk from these PPARγ-deficient mothers may have higher levels of oxidized free fatty acids (FFAs), which may be the major inflammatory lipids. Ingestion of this inflammatory milk causes a systemic inflammatory and toxic response in the nursing neonates that is manifested as skin inflammation, fur loss/alopecia, growth retardation, anemia, and lipid accumulation in multiple tissues such as skin and liver. However, overexpression of an active form of PPARγ in the MECs did not result in any defect in mammary gland development [102], suggesting that possibly PPARγ in hematopoietic and endothelial cells, rather than MECs, plays a critical role in the lactating mammary gland. Interestingly, hair follicle stem cell-specific PPARγ deletion causes scarring alopecia [103]. In summary, maternal PPARγ is pivotal for maintaining the quality of milk and protecting the nursing newborns by suppressing the production of inflammatory lipids. These findings reveal a novel role for PPARγ in the postnatal maternal–offspring interaction via the mammary gland, and further support the idea that milk lipids provide not only calories, but also signaling molecules that regulate the development of the newborns.

3.2 VLDLR

VLDLR is a member of the low-density lipoprotein receptor (LDLR) family. It is highly expressed in tissues with active TAG metabolism such as adipose tissue, heart, and skeletal muscle, but absent from the liver [104, 105]. VLDLR is known to regulate TAG metabolism via mediating the uptake of its ligand very low-density lipoprotein (VLDL) by peripheral tissues [106, 107]. It also modulates brain development by forming a heterodimer with ApoER2 [108]. Activation of VLDLR by its ligand Reelin (Reln) triggers downstream signaling events that modulate neuronal functions [108, 109]. In addition, VLDLR has protective roles against obesity, insulin resistance and inflammation [110, 111]. Maternal VLDLR deletion in mice causes the production of defective milk containing diminished levels of platelet-activating factor acetylhydrolase (PAFAH) [85]. Detailed analysis shows that VLDLR deletion significantly impairs the expression of phospholipase A2 group 7 (PLA2G7) in macrophages, leading to decreased PAFAH secretion in milk. Platelet-activating factors (PAFs) represent a class of potent pro-inflammatory lipids that are present in neonates whose immune system is not fully developed, and is elevated in infants suffering inflammatory disorders such as necrotizing enterocolitis [3, 112]. Previous studies show that milk contains the secreted form of PAF degradation enzyme PAFAH, which may be critical to suppress the proinflammatory activity of PAF in the nursing neonates [112–114]. Ingestion of the PAFAH-deficient milk from VLDLR KO mother leads to PAF accumulation in the nursing pups [85]. As a consequence, the nursing neonates suffer from alopecia, anemia, growth retardation, and systemic inflammation. Oral PAFAH supplementation to the pups can rescue the neonatal toxicity. Therefore, we have identified a novel anti-inflammatory role of VLDLR in promoting macrophage PAFAH secretion, and demonstrate its physiological significance in ensuring milk PAFAH levels and protecting the nursing newborns from systemic inflammation.

Provocatively, our recent study reveals that maternal toxic milk can exert long-term impact on the offspring to adulthood. The abnormal milk from VLDLR KO mice blunts the differentiation of the bone-resorbing cell type osteoclast and consequently causes osteopetrosis in the offspring up to 3 month of age [87]. Our detailed pharmacological and genetic rescue experiments reveal that these milk defects are largely due to an excessive activity of mammalian target of rapamycin (mTOR) signaling in the adipocytes, which can be reversed by maternal rapamycin treatment during lactation [87]. Moreover, we find that these milk defects are also contributed by an increased expression of the rate-limiting enzyme in the cholesterol biosynthetic pathway 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and consequently elevated levels of cholesterol precursors in the milk [87]. Together, these findings further uncover the cellular, molecular and biochemical mechanisms for how maternal VLDLR ensures milk quality and protects the offspring from both immediate and long-term abnormalities.

3.3 Adiponectin

Adiponectin is an adipokine playing important roles in lipid and glucose metabolism [115–117]. Increasing evidence suggests that altered adiponectin levels are associated with inflammatory disorders, which can further exacerbate the metabolic syndrome [118]. Our recent study suggests that adiponectin is also essential for the normal development and function of lactating mammary gland. Interestingly, both too much adiponectin as in the TG mice and too little adiponectin as in the KO mice cause inflammatory milk secretion and neonatal inflammation but with different developmental and metabolic defects in the lactating mammary glands [86]. The glands from adiponectin KO mice exhibit an early involution due to more apoptosis and less ductal/alveolar structures; whereas the glands from adiponectin TG mice display a reduced alveolar expansion with more adipocytes during pregnancy and lactation. Consequently, these developmental defects both lead to inefficient lactation and reduced milk production evidenced by lower body weight in the pups nursed by adiponectin KO and TG dams. In addition, milk quality is compromised by both maternal adiponectin deletion and overexpression. Ingestion of these toxic milk leads to systemic inflammation in the pups, manifested as transient fur loss [86]. Adiponectin deficiency triggers leukocyte infiltration and production of proinflammatory cytokines in the lactating mammary gland. Moreover, the expression of several enzymes that produce proinflammatory lipids such as prostaglandin and leukotriene, including cyclooxygenase 2 (COX2), arachidonate 5-lipoxygenase (ALOX5) and Ephx1, is higher in adiponectin KO glands. Consistent with these observations, the levels of oxidized FAs are increased in the skin of the pups nursed by adiponectin KO dams. In contrast, adiponectin overexpression increases lipid accumulation in the lactating mammary gland, resulting in excessive long-chain saturated fatty acids (LcS-FAs) in milk. Inflammatory lipids can affect immune cells and immunity through various mechanisms. One major understanding on how LcS-FAs and lipids cause inflammation is through the activation of toll-like receptors (TLRs) [119–121]. Interestingly, in both cases, the inflammation and alopecia in the pups can be rescued by TLR2/4 deletion because TLR2/4 double KO pups are resistant. These results indicate that both increased abundance in LcS-FA and increased sensitivity to LcS-FA due to elevated inflammatory cytokines can trigger a systemic inflammation in the offspring via TLR2/4-dependent signaling. Our findings reveal adiponectin as a dosage-dependent regulator of lactation homeostasis and milk quality that critically control inflammation in the nursing neonates. Furthermore, these results suggest that inflammatory infantile disorders may result from maternal adiponectin dysregulation that can be treated by TLR2/4 inhibition. Maternal adiponectin is also a key genetic program that controls the normal development of mammary gland as well as metabolic and immune homeostasis during lactation to ensure normal milk production and their composition and prevent neonatal inflammation.

3.4 Western High Fat Diet

Consumption of a western HFD is highly associated with the current epidemic of metabolic disorders such as obesity and diabetes. It is increasingly recognized that peripheral as well as central activation of inflammatory pathway related to consumption of HFD is linked to these metabolic disorders [118, 122–124]. Western HFD not only causes metabolic consequences to adult individuals consuming it, but maternal consumption of western HFD during sensitive prenatal and postnatal development (e.g. pregnancy and lactation) can exert long-lasting consequences on the offspring both peripherally or centrally causing various metabolic disorders [125–128]. In addition to the in utero effects during pregnancy, this kind of early life programming can also be mediated through milk during lactation. Our recent study reveals that maternal HFD consumption in mice causes the production of milk that contains not only higher fat content but also excessive LcS-FAs [84]. Studies have showed that LcS-FAs (C16:0 and C18:0) but not unsaturated FAs or medium/short-chain FAs (C8:0–C12:0) can specifically activate proinflammatory pathway via TLRs [119, 129–131]. The pups that ingest this inflammatory milk from HFD mother exhibit an increased body weight, and show ceramide accumulation and systemic inflammation, manifested as alopecia [84]. Similar as the findings from adiponectin study [86], the neonatal toxicity in this case also requires TLRs, because genetic TLR2/4 deletion or pharmacological TLR4 inhibition in the pups confers resistance. In summary, maternal western HFD feeding causes the secretion of inflammatory milk that contains excessive LcS-FAs, which activate the TLRs signaling pathway to elevate the levels of ceramide as well as proinflammatory cytokines and enzymes, consequently triggering neonatal toxicity. These findings unravel maternal HFD-induced inflammatory milk secretion as a novel aspect of the metabolic syndrome at the maternal-offspring interface. Furthermore, studies show that maternal consumption of western HFD can also exert other long-lasting consequences on the offspring such as neurodevelopmental disorders [132–134], disrupted gut microbiota [134, 135], liver diseases [136–139], impaired islet vascularization [140], and atherosclerosis development [141].

4. Conclusions and Perspectives

Milk quality impacts the health of the offspring, as it not only regulates their postnatal development, but also influences their propensity to develop chronic diseases in adulthood. Therefore, the understanding of the genetic and biochemical mechanisms that ensure proper milk composition will provide new insights for human physiology and diseases [142]. Latest research uncover that maternal genetic or dietary defects can lead to dysregulated lipid metabolism in the mammary gland during lactation and the secretion of toxic milk with abnormal milk lipid composition that causes various disorders in nursing newborns. Thus, toxic milk will greatly compromise the health of both breast-fed infants and consumers of dairy products. As such, milk defects may represent previously unrecognized etiology for mysterious infantile diseases. Future studies are required to further elucidate the genetic, dietary and environmental factors that affect the ability of the mother to produce sufficient milk with appropriate compositions. In addition, studies are needed to explore the mechanisms, such as via epigenetic regulation, for how defects in maternal milk composition exert long-term consequences in the offspring and make them more vulnerable to various chronic diseases. Finally, an equally important question is how offspring genetic defects may render them incompatible with normal breast milk and generate inflammatory disorders. To that end, we have identified mitochondria complex I as a key factor in the offspring that is required for the postnatal metabolic adaptation to milk consumption [143]. These findings suggest a mother-infant co-evolution in which the offspring adapts its genetic makeup to match the mother’s milk composition and vice versa. Ultimately, elucidation of the mechanisms by which mother’s milk nourishes and protects the newborns is fundamentally important in order to design better infant formula and novel diagnostic/therapeutic strategies for infantile and chronic diseases.

Abbreviations

ACC

acetyl-CoA carboxylase

ADPH

adipophilin

Akt/PKB

protein kinase B

ALOX5

arachidonate 5-lipoxygenase

BTN1A1

butyrophilin subfamily 1 member a1

CIDEA

cell death-inducing DNA fragmentation factor α-like effector A

COX2

cyclooxygenase 2

DGAT1

diacylglycerol transferase 1

EPHX1

microsomal epoxide hydrolase

FA

fatty acid

FASN

fatty acid synthase

FFA

free fatty acids

HFD

high-fat diet

HMGCR

3-hydroxy-3-methylglutaryl coenzyme A reductase

IGF1

insulin-like growth factor 1

INSIG1

insulin-induced gene 1

IRS

insulin receptor substrate

KO

knockout

LcS-FA

long-chain saturated fatty acids

LDLR

low-density lipoprotein receptor

LXR

liver X receptor

MCFA

medium-chain fatty acid

MEC

mammary epithelial cell

MFG

milk fat globule

mTOR

mammalian target of rapamycin

NAFLD

nonalcoholic fatty liver disease

NHR

nuclear hormone receptor

PAF

platelet-activating factor

PAFAH

platelet-activating factor acetylhydrolase

PKN1

protein kinase N1

PLA2G7

phospholipase A2 group 7

PPAR

peroxisome proliferator-activated receptor

PRL

prolactin

PRLR

prolactin receptor

RELN

Reelin

S14

thyroid hormone responsive spot 14

S14R

S14 related gene

SCAP

SREBP cleavage-activating protein

SCD

stearoyl-CoA desaturase

SLC25A1

mitochondrial citrate transporter

SRE

sterol response element

SREBP

sterol regulatory element-binding protein

TAG

triacylglyceride

TG

transgenic

TLR

toll-like receptor

TZD

Thiazolidinedione

VLDL

very low-density lipoprotein

VLDLR

very low-density lipoprotein receptor

XOR

xanthine oxidoreductase

12-LO

12-lipoxygenase