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Table 2 Outline of DE genes which are relevant to fatty acid metabolism based on Gene Ontogeny (GO) biological function and literature searches

From: The application of transcriptomic data in the authentication of beef derived from contrasting production systems

Gene Symbol

GO Terms –Biological Process (selected terms related to lipid metabolism)

Description of gene function

Evidence relating the gene to meat quality, FA metabolism and regulation

CPT1B

fatty acid beta-oxidation - GO:0006635

carnitine shuttle - GO:0006853

long-chain fatty acid transport - GO:0015909

cellular lipid metabolic process - GO:0044255

regulation of fatty acid oxidation - GO:0046320

The CPT1B gene encodes an enzyme which is part of the carnitine shuttle, responsible for transferring long-chain FA across the barrier of the inner mitochondrial membrane to gain access to the enzymes of β-oxidation. CPT1B is the muscle isoform but it is also expressed in adipocytes.

Widely reported to be regulated by PPARδ in skeletal muscle [29].

Up-regulated in the muscle of grazing lambs relative to those reared indoors [30] and also in the muscle of Barrosã breed relative to the Alentegjana bulls (a breed which possesses higher fatty acid proportions within the subcutaneous adipose tissue) [31].

PLIN 5

 

Members of the perilipin family including PLIN5, coat intracellular lipid storage droplets and protecting them from lipolytic degradation [23].

Fatty acids reported to regulate PLIN5 through the activation of PPARδ in muscle [32].

Muscles over-expressing PLIN5 displayed a 44.8 % increase in fatty acid oxidation [33].

C/EBPα promotes transcription of PLIN5 in pigs [34]

FYN

 

FYN, encodes a tyrosine-specific kinase that belongs to the Src kinase family and is known to regulate cell proliferation and ion channel activity. The protein associates with the p85 subunit phosphatidylinositol 3-kinase and interacts with the FYN-binding protein [35].

FYN has been reported to regulate the activity of the adipogenic transcription factor STAT5a which subsequently initiates the expression of the master adipogenic transcription factors PPARγ and C/EBPα (Tse et al., 2013).

PUFAs, arachidonic acid and eicosapentaenoic acid reported to inhibit Fyn palmitoylation, thereby blocking Fyn localisation to detergent-resistant membranes in T cells [36]

Mice null for Fyn display reduced adipose mass associated with decreased adipocyte cell size. In parallel, a substantial reduction in fasting plasma glucose, insulin, triglycerides, and free fatty acids is evident concomitant with decreased intra-hepatocellular and intra-myocellular lipid accumulation [37].

ABCA1

phospholipid binding - GO:0005543

phospholipid transporter activity - GO:0005548

cholesterol binding - GO:0015485

cholesterol transporter activity - GO:0017127

apolipoprotein binding - GO:0034185

apolipoprotein A-I binding - GO:0034186

apolipoprotein A-I receptor activity - GO:0034188

ABCA1 encodes a membrane-associated protein and is a member of the superfamily of ATP-binding cassette (ABC) transporters, which transport various molecules across extra- and intracellular membranes. ABCA1 has been referred to as the gatekeeper of the reverse cholesterol transport pathway whereby excess cholesterol in peripheral tissues is transported to the liver for elimination from the body [38]

Reported to be regulated by PPARδ in cultured human muscle [24] and in human myotubes [21].

Expression of ABCA1 was found to be correlated with beef traits in the LD muscle between 1 and 24 Months in Chinese Red Steppes [39]

A SNP c27113G > A present in the ABCA1 gene was reported to have significant associations with conjugated linoleic acid (CLA) in the muscle of a Waagyu x Limousin reference population [40]

miR-758, miR-26 and miR-106b all reported to target ABCA1 [41]

KLF11

 

KLF11 is a ubiquitously expressed transcription factor which contains a Krüppel-like 3 zinc finger motif at the C-terminal end of the protein. KLF11 binds GC rich Sp1-like sequences to regulate gene expression and inhibit cell proliferation [42]. Although KLF11 was initially introduced as a TGF-β inducible gene, several studies have described its up-regulation by a range of growth factors, cytokines and hormones [43]

Reported to be regulated by PPARδ in human myotubes [21]

FABP5

fatty acid binding - GO:0005504

lipid binding - GO:0008289

FABP5 is expressed in epidermal cells and adipocytes and belongs to a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and have roles in fatty acid uptake, transport, and metabolism [44]

FABP5 shuttles ligands from the cytosol to the nuclear receptor PPAR thereby enhancing the transcriptional activity of the receptor [45]

FABP5 was differentially expressed between animals exhibiting divergent patterns of fatty acid composition in LT muscle [46]

Protein expression correlated with subcutaneous fat thickness in British-continental steers on diets with differing levels of fat [47]

EIF4EBP1

 

Encodes a translation repressor proteins which interacts with eukaryotic translation initiation factor 4E (eIF4E), thereby repressing translation. It can be phosphorylated in response to various signals, including insulin.

Differentially expressed in LD muscle in Jinhua (high oxidative metabolism and adipogenesis) and Landrace (low oxidative metabolism and adipogenesis) pigs [48]

Some evidence indicates that this class of translation repressor protein is inhibited by mTORC1 and important for the regulation of PPAR-γ and C/EBPs by mTORC1 [49]

FZD4

 

FZD4 is a member of the frizzled gene family of receptors. Most frizzled receptors are coupled to the beta-catenin canonical signalling pathway and may play a role as a positive regulator of the Wnt signalling pathway which plays a major role in differentiation and patterning during embryogenesis as well as regulating cell proliferation in adult tissues [50]

Expression of FZD4 increases gradually during adipogenesis in human adipose tissue-derived stem cells and decreases in response to the anti-adipogenic agent isorhamnetin [51]

FCGRT

  

Up-regulated in hepatocytes cultured with the PPARδ agonist (KD3010) relative to the control [28]

CCL14

 

CCL14 is a chemokine that promotes trophoblast migration. CCL14 to be a potent promoter of breast cancer angiogenesis and metastasis [52]

Found to be induced by PPAR in primary human hepatocytes [22]

ACSL3

fatty acid biosynthetic process - GO:0006633

triglyceride biosynthetic process - GO:0019432

low-density lipoprotein particle assembly- GO:0034379

LC fatty-acyl-CoA biosynthetic process - GO:0035338

cellular lipid metabolic process - GO:0044255

long-chain fatty acid import- GO:0044539

The formation of acyl-CoA from fatty acid, ATP, and CoA is catalysed by acyl-CoA synthetase (ACS). This reaction an essential reaction in mammalian FA metabolism. Acyl-CoAs produced by ACS are mainly utilised both in the synthesis of cellular lipids and in degradation via the β-oxidation system for energy production. In addition to the production of acyl-CoA, ACS also facilitates the cellular uptake of long-chain fatty acids [53]. ACSL3 utilizes arachidonate and eicosapentaenoate most efficiently among the C16-C20 unsaturated fatty acids [54].

SNP associated with this gene was significantly associated with the percentages of oleic fatty acid and MUFA [55]

Established as a PPARα target gene in bovine cell line [56]

Reported to be regulated by PPARδ activation in human myotubes [21]

GPIHBP1

lipid transport - GO:0006869

cholesterol homeostasis - GO:0042632

positive regulation of lipoprotein lipase activity - GO:0051006

triglyceride homeostasis - GO:0070328

GPIHBP1 is a capillary endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons as transfection of mouse Gpihbp1 in CHO cells conferred the ability to bind LPL and chylomicrons [57]

Established as a protein of capillary endothelial cells and the principal binding site for LPL on endothelial cells, responsible for transporting LPL to the capillary lumen [58]

Using transfected Chinese hamster ovary (CHO) it was demonstrated that mouse Gpihbp1 bound to radiolabeled high density lipoprotein (HDL), and selectively bound the lipid component of HDL, but not cholesterol or protein [59]

STK40

 

STK40 encodes a protein of 435 amino acid residues and contains a serine/threonine kinase domain. Transcript and protein levels of Stk40 were found to be up-regulated and maintained at high levels during the process of spontaneous embryoid-body (EB) formation [60]

In a GWAS > 1,000 human subjects lipoprotein measurements in a SNP rs3007220 in an intron within STK40 was associated with HDL cholesterol concentrations [61]

ST6GALNAC4

 

The protein encoded by ST6GALNAC4 is a type II membrane protein that catalyses the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates and is normally found in the Golgi apparatus but can be proteolytically processed to a soluble form [62]

Differentially expressed in the adipose tissue of rat supplemented with genistein, a phytoeastrogen known to up-regulate the activity of the transcription factor PPARα [26]

ST6GALNAC4 is amongst one of the genes which was DE in response to the β 2-agonist, clenbuterol in pig adipose tissue and it was concluded that this gene may (along with other factors) contribute to adipose tissue reduction [63]

LDLR

lipid metabolic process - GO:0006629

cholesterol metabolic process - GO:0008203

regulation of triglyceride biosynthetic process -GO:0010867

phospholipid transport- GO:0015914

intestinal cholesterol absorption - GO:0030299

cholesterol transport- GO:0030301

low-density lipoprotein particle clearance - GO:0034383

lipoprotein metabolic process - GO:0042157

lipoprotein catabolic process - GO:0042159

cholesterol homeostasis - GO:0042632

cholesterol import- GO:0070508

The LDLR is a major determinant of plasma cholesterol levels. This cell surface receptor is expressed primarily in liver and removes cholesterol-carrying LDL from plasma by receptor-mediated endocytosis [64]

The transcription of LDLR is primarily under the control of the transcription factor SREBP-2 [65]

LDL-bound LDLR is endocytosed through a clathrin-dependent pathway and, after releasing in the late endosome, the LDLR is either recycled back to the plasma membrane or degraded in the lysosome [66]

ADH is associated with mutations in the genes encoding LDLR and its ligand apolipoprotein B (APOB) [67]

Expression correlated with IMF % in pigs [68]

Rare variants of LDLR have significant associations with familial hypercholesterolemia [69]

PPARÉ£ activation has been shown to induce LDLR expression and enhance LDL cholesterol metabolism in a hepatic cell line [27]

The transcription of LDLR is primarily under the control of SREBP-2 [65]

MSMO1

fatty acid metabolic process- GO:0006631

fatty acid biosynthetic process-GO:0006633

cholesterol biosynthetic process -GO:0006695

Sterol-C4-methyl oxidase-like protein contains a set of putative metal binding motifs with similarity to that seen in a family of membrane desaturases-hydroxylases. The protein is localized to the endoplasmic reticulum membrane and is believed to function in cholesterol biosynthesis [70]

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