Accepted Manuscript

Genes, transcription factors and enzymes involved in lipid

metabolism in fin fish

Christian Larbi Ayisi, Cheng Yamei, Jin-Liang Zhao

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DOI: doi:10.1016/j.aggene.2017.09.006
Reference: AGGENE 57
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Received date: 15 June 2017
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Accepted date: 27 September 2017

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 ACCEPTED MANUSCRIPT

Genes, Transcription factors and enzymes involved in lipid

metabolism in fin fish

Christian Larbi Ayisi, Cheng Yamei and Jin-Liang Zhao*

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Key Laboratory of Freshwater Fishery Germplasm Resources, Ministry of Agriculture,

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Shanghai Ocean University, 999 Huchenghuan Road, Shanghai 201306, P. R. China
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*
Corresponding author: Jin-Liang Zhao
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Tel: (+86) 21 61900435

Fax: (+86) 21 61900405

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E-mail: jlzhao@shou.edu.cn
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1. Introduction

In fish, dietary lipids are an important source of essential fatty acids (FA) for regular

growth, health, reproduction and bodily functions (Turchini et al., 2009). Dietary fatty

acid composition is known to have a modulatory effect on the enzyme activity

governing the fatty acid bioconversion pathways of cultured teleost species

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(Thanuthong et al., 2011).

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FA regulate the hepatic expression of genes involved in fatty acid desaturation and

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elongation (Zheng et al., 2004). Many key enzymes and transcriptional factors play

key roles in lipogenesis and lipolysis (Zheng et al., 2013). These enzymes include
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peroxisome proliferator-activated receptor-α (PPAR-α), peroxisome
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proliferator-activated receptor β (PPAR-β), Lipoprotein lipase (LPL), Fatty acid

binding protein 3 (fabp3) and malic enzyme. Other genes/enzymes such as fatty acid
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synthase (FASN), and acetyl-CoA carboxylase (ACC), carnitine palmitoyltransferase I

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(CPT I), hormone-sensitive lipase (HSL) and adipose triacylglyceride lipase (ATGL)
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are known to play important roles in the break down and utilization of lipids (Elliott

and Elliott, 2009).

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Poly and monounsaturated fatty acids (FA) are natural ligands that activate PPARs in

teleost (Colliar et al., 2011). EPA can bind to PPAR-α with higher affinity than

saturated fatty acid (SFA), monounsaturated fatty acid (MUFA) and n−6

polyunsaturated fatty acid (n−6 PUFA) (Desvergne and Wahli, 1999). PPARα

activation by n-3 PUFA may induce the expression of lipolytic genes, and increase the

activity of enzymes related in lipid metabolism (Peng et al., 2014). For instance,

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based on the lipid source, there is a direct correlation between the elongases

responsible for the synthesis of LC-PUFA and the transcript expression of desaturases

(Morais et al., 2011a; Glencross et al., 2015; Xue et al., 2015).

The liver is a major site with respect to lipolysis and lipogenesis (Pierron et al., 2007)

hence the relationship between gene expression of lipid and FA metabolism-related

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transcripts in the liver is worth investigating from a nutrition and production

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perspective.

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Having adequate knowledge with respect to the molecular mechanisms that regulates

the metabolism and utilization of dietary lipids adds additional elements to

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understanding the feeding and growth response in fish when fed with a particular lipid.
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In this paper, we review the genes that are involved in lipid metabolism as well as

how these genes are altered when different lipid sources are used in place of the
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traditionally used fish oil.

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2. Genes, signaling factors and enzymes involved in lipid metabolism

As stated earlier above, many enzymes, genes and transcriptional factors are involved
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in the metabolism of lipids/fatty acids. In this section, we discuss the roles of some of

these enzymes, genes and transcriptional factors. In table 1, we give a list of some

enzymes, genes as well as transcriptional factors involved in lipid metabolism and the

roles.

TABLE 1

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2.1 The PPAR signaling pathway (PPAR)

PPAR is known to respond to lipids and elicit transcriptional changes on genes

involved in lipid metabolism in mammals. PPARs are members of the nuclear

receptor super family of ligand activated transcription factors (Poulsen et al., 2012),

PPAR-α and PPAR-β are responsible for regulating fatty acid β-oxidation (Varga et al.,

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2011). Whereas PPAR-β is involved in the activation of lipid utilization by regulating

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the expression of target genes encoding enzymes responsible for β-oxidation (Dressel

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et al., 2003), PPAR-α catabolise FA by regulating how several key enzymes involved

in FA oxidation are expressed (Li et al., 2015). Replacing fish oil with soybean oil
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affected the mRNA expression (lpl and PPARα) of juvenile turbot (Scophthalmus
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maximus L.) (Peng et al., 2014).

PPARγ, another member of PPAR family, is involved in adipocyte function and

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differentiation, lipid storage by adipocytes, and glucose responsiveness (Francis et al.,

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2003).
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2.2 Lipoprotein (LPL)

LPL is considered an important factor in lipolysis (Tian et al., 2013) because it serve
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as a “gate keeper” for the uptake of FA into organs (Greenwood, 1985). Lpl has been

hypothesized as an enzyme that might determine how dietary lipids are partitioned for

storage or utilization because it’s a rate limiting enzyme in the provision of fatty acids

to tissues (Saera-Villa et al., 2005).

LPL is a member of the lipase gene super family (Wong and Schotz, 2002). A large

body of evidence from both human studies and animal models suggests that the level

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of LPL expression in a given tissue is the rate- limiting process for the uptake of

triacylglycerol (TAG) derived FA (Preiss-Landl et al., 2002). The role of LPL is to

hydrolyse TAG that circulates in the TG-rich lipoprotein particles, thus enabling the

delivery of fatty acids to the tissue (Fielding and F rayn, 1998). LPL gene expression

is regulated differentially according to the nutritional state and hormonal levels

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according to the needs of the tissue for fatty acids (Fielding and Frayn, 1998). Liang

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et al. (2002) suggested that the effect of dietary fatty acids on LPL gene expression is

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tissue specific and related to the feeding conditions of red sea bream. LPL also act as

the primary enzyme required for chylomicron (CM) and very low-density lipoprotein
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(VLDL) catabolism. The physiological actions of LP L in the catabolism of CMs and
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VLDL and in the production of most of the lipids and apolipoproteins that form high

density lipoprotein (HDL) have been understood for more than two decades (Eckel,
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1989), and LPL regulates the plasma levels of TAG and HDL (Merkel et al., 2002).
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Also, LPL hydrolyze triglycerides which come from the diets and release fatty acids
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which are then taken up by the adipocytes and accumulate in the form of droplets.

2.3 Fatty acid binding protein (FABP)

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FABP play an intermediary role in orchestrating the gene transcription involved in

lipid homeostasis (Lu et al., 2014). Distel et al. (1992) reported that FABP gene

expression was regulated by PUFA. It is also known that FABPs can act specifically

and cooperatively with LA to modulate the growth of hepatocytes (Keler et al., 1992).

FABP in general is noted for the intracellular transport of FA. FABPs are highly

conserved in cytoplasmic proteins that usually have low molecular weights ranging

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between 14 and 15kDa (Tocher, 2003; Schulz, 2008). Also, they perform functions

such as sequestering FA and other lipophilic compounds. It also transport and store FA

to the mitochondria (Olivares- Rubio and Vega-Lopez, 2016).

2.4 Malic enzyme (ME)

ME is involved in the regulation of the lipid metabolism (Guay et al., 2007). Malic

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enzyme is essential in the synthesis of fatty acids. It is involved in catalyzing NADPH

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production which is essential for hepatic fatty acid biosynthesis (Chou and Shiau,

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1996). Malic enzyme catalyses the reversible decarboxylation of malate to form

pyruvate in the presence of NAD or NADP and a divalent cation (Mn2+ or Mg2+)
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(Niedźwiecka and Skorkowski, 2013).
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2.5 Fatty acid synthesase (FASN)

FASN plays a key role in the opposite process of de novo lipogenesis by converting
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acetyl-CoA and malonyl-CoA into the final end product, palmitate, which is
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subsequently esterified into TAG and stored in adipose tissue (Tian et al., 2013).
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2.6 Acetyl-CoA carboxylase (ACC)

ACC is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of

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acetyl-CoA to malonyl-CoA, the rate- limiting step in fatty acid biosynthetic pathway

(Barber et al., 2005; Tong, 2005). This enzyme is one of the acylCoA desaturases

representing the first regulatory step in the formation of long-chain unsaturated fatty

acids (Enoch et al., 1976), is responsible for introduction of the first double bond

between carbons 9 and 10 of palmitoyl (16:0)- and stearoyl (18:0)-CoA to form the

mono- unsaturated palmitoleic acid (16:1) and oleic acid (18:1), respectively (Jeffcoat

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et al., 1977). Acetyl-CoA carboxylase (ACC) play important roles such as the

synthesis of fatty acid synthesis through the ACCa. In addition to this, it also regulates

fatty acid oxidation through the ACCb (Cheng et al., 2011).

2.7 Stearoyl-CoA desaturase (SCD)

SCD is known for their roles in synthesizing unsaturated fatty acids (Ardiyanti et al.,

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2012). SCD synthesizes oleate necessary for the biosynthesis of triglycerides and

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other lipids (Miyazaki et al., 2004). It plays critical role in the transformation of

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saturated fatty acids to unsaturated fatty acids by inducing the first double bond

between the C9 and C10 positions in palmitoyl-CoA (16:0) and stearoyl-CoA (18:0) .
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this is then converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively
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(Hsieh et al., 2004).

2.8 Carnitine palmitoyltransferase (CPT)

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Due to the ability of CPT to catalyse the conversion of fatty acyl-CoAs into fatty
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acylcarnitines for entry into the mitochondrial matrix, it is deemed as the main
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regulatory enzyme in mitochondrial fatty acid oxidation because it catalyses the

conversion (Kerner and Hoppel, 2000). The mechanisms involved in CPT regulation
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and consequently mitochondrial β-oxidation of fatty acids is dependent on various

nutrients. CPT is regulated through a pparα- independent pathway (Kerner and Hoppel,

2000; LeMay et al., 2005; Zheng et al., 2013).

2.9 Sterol-regulator element-binding protein (SREBP)

SREBP is a main regulator of fatty acid/lipid and cholesterol biosynthesis (Minghetti

et al., 2011). Whereas SREBP1 regulates several lipogenic genes, SREBP2 primarily

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regulates the transcription of cholesterogenic enzymes (Jeon and Osborne, 2012).

2.10 6-phosphogluconate dehydrogenase (6PGD) and glucose 6-phosphate

dehydrogenase (G6PD)

6PGD as well as G6PD are major regulatory enzymes involved in the production

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NADPH. They are also important in the biosynthesis of fatty acid (Chen et al., 2013).

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Glucose 6-phosphate dehydrogenase and 6-Phosphogluconate dehydrogenase are the

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first and third enzymes respectively in the pentose phosphate pathway.

6-Phosphogluconate dehydrogenase catalyze the conversion of 6-phosphogluconate to

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D-riboluse-5-phosphate in the presence of NADP+ whiles Glucose 6-phosphate
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dehydrogenase is responsible for the production of NADPH.

2.11 Microsomal triacylglycerol transfer protein (MTP)

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Due to MTPs responsibility for liver lipoprotein function and assemblage, it is

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directly involved in lipid distribution (Borges et al., 2013). MTP regulates the
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secretion of VLDL in hepatic tissues. It also modulates the transport of triglyceride

across the endoplasmic reticulum (Hussain et al., 2008).

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2.12 Hormone Sensitive Lipase (HSL)

HSL is a rate- limiting enzyme and is involved in the breakdown of TAG into

diacylglycerol and then into monoacylglycerol (Holm et al., 2000). It catalyses the

rate limiting step in lipolysis in adipose tissue as well as accessing the lipid droplet

and hydrolyze the triglycerides into glycerol and fatty acids (Lafontan and Langin,

2009). As mentioned above, HSL catalyzes the rate- limiting step in the mobilization

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of FA, thus determining the supply of energy substrates in the body. Consequently,

any variation in HSL expression will decisively modulate the proportion of lipid

mobilization (Chen et al., 2014).

2.13 Liver X receptor (LXR)

LXR is important in controlling the intermediary metabolism that mediates

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cross-regulation between sterol metabolism and fatty acid (Jakobsson et al., 2012). It

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plays this intermediary role in lipid homeostasis, by orchestrating the gene

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transcription of the enzymes involved in these pathways (Spiegelman and Flier, 2001)

Binding oxysterol ligands as well as catabolic products of cholesterol are responsib le

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for the activation of LXR activity (Reschly et al., 2008). LXR ligands can be
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antagonized by fatty acids (Cruz-Garcia et al., 2012) and is responsible for the

regulation of genes involved in synthesis of fatty acids (Repa et al., 2000; Schultz et
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al., 2000).
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2.14 Elongases of very long-chain fatty acids (ELOVL)

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One of the major enzymes in the pathways for the elongation of C18 PUFAs to

C20/22 unsaturated fatty acids is ELOVL (Simopoulos, 2000). ELOVL are the initial
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and rate-limiting enzymes responsible for the condensation of activated fatty acids

with malonyl-CoA required for biosynthesis of long-chain fatty acids (Nugteren,

1965). There are seven ELOVL(s) (ELOVL 1-7) and basically differ with respect to

their specificity of substrate (Jakobsson et al., 2006).

Among these elongases, the ELOVL 5 function by adding two carbons to their

respective C18, C20 or C22 PUFA substrates, and preferentially elongates C18/C20

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PUFA substrates (Leonard et al., 2002).

2.15 Apolipoproteins

Approximately 60-75% of the protein content of high density lipoprotein is made up

of Apolipoproteins (Asztalos and Schaefer, 2003; Kontush et al., 2015).

Apolipoprotein is basically produced in the liver as well as intestine and secreted as a

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peptide (Brunham et al., 2006; Sliwkowski and Windmueller, 1984; Wu and

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Windmueller, 1979). In addition to Apolipoproteins transporting lipids, it also target

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lipoproteins to specific tissues throughout specific binding to lipoprotein receptors

and activation of lipolytic enzymes (Gursky, 2005). There are five classes of
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apolipoproteins, A through E, according to their structure and function, similarly to
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mammals (Chapman, 1980).

2.16 Fatty acid translocase/cluster of differentiation 36 (FAT/CD36)

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The fatty acid translocase (FAT/CD36), now officially being designated as the
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scavenger receptor B2 (SR-B2) (Prabhudas et al. 2014). FAT/CD36 is a plasma

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membrane fatty-acid transport protein, that is located on mitochondrial membranes. It

is responsible for the regulation of palmitate oxidation. (Brennan et al. 2011).

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FAT/CD36 binds long-chain fatty acids with high affinities and functions as a major

facilitator of fatty acid release from albumin and subsequent uptake in muscle and

adipose tissues, which is influenced by the presence of caveolin-1 and lipid rafts

(Ehehalt et al. 2008). It is one of the most important FA transporters associated with

LCFA trans- membrane uptake as it has been reported in humans (Luiken et al. 2016)

and different teleost fish species (Torstensen et al. 2009; Zhou et al. 2010; Fink et al.

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2015).

2.17 Glycerol-3-phosphate acyltransferase (GPAT)

According to Castro et al. (2016), GPAT plays essential roles in the initial steps of

glycerol-3-phosphate pathways. The synthesis of triacylglycerol (TAG) is initiated by

the acylation of glycerol-3-phosphate (G3P) with a long-chain acyl-CoA in a

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rate- limiting step catalyzed by glycerol-3-phosphate acyltransferase (GPAT)

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(Alves-Bezerra et al. 2017). It is also known to be a competitor with CPT1 for

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acyl-CoAs at the outer mitochondrial membrane of tissues.

3.0 An overview of lipolysis, lipogenesis, β–oxidation and Transport of lipids

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The metabolism and deposition of lipids is a complex phenomenon in fish. It involves
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complex processes such as lipogenesis, β–oxidation and Biosynthesis of long–chain

PUFA. Whereas tissues such as the muscle, adipose tissue, ovary and heart play
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essential roles in the metabolism and deposition of lipids in fish (Zheng et al., 2013),
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the liver is the main site where lipolysis and lipogenesis occur (Pierron et al., 2007).
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In this section we give a brief description of the processes involved in lipid

metabolism.
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3.1 lipolysis

The biochemical pathway responsible for the sequential hydrolysis of triacylglycerol

(TAGs) stored in cellular lipid droplets is termed as lipolysis (Bolsoni- Lopez and

Alonso, 2015; Sun et al., 2016). It is an important process in the metabolism of lipids.

Three specific lipase; hormone sensitive lipase, monoacylglycerol lipase as well as

adipose triacylglycerol lipase are needed to complete the lipolysis process (Sun et al.,

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2016).

Genes such as HSL and ATGL regulate lipolysis in tissue in a step-wise fashion

(Gaidhu et al., 2010; Figueiredo-Silva et al., 2012). ATLG activates lipolysis by

cleaving the first FA from TAG. HSL later acts on diacylglycerol (DAG) by releasing

two additional FAs and one glycerol molecule (Lafontan and Langin, 2009). In fig 1,

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we summarize the lipolytic mechanism. During lipolysis, lipoproteins such as

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very- low-density lipoprotein (VLDL) carry triglycerides to tissues such as the muscle

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and adipose tissue using the blood as media. By this the fatty acids released bind

albumin in the blood leading to its entry of the mitochondria where β–oxidation
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occurs to give energy.
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FIG 1

3.2 lipogenesis
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The process by which lipogenesis takes place in fish was summarized by Schulz
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(2008) (Fig 2). As mentioned earlier, apart from the liver which is the main site of
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lipogenesis (Sargent et al., 2012), other tissues such as muscle and subcutaneous

tissues are known for lipid deposition (Weil et al., 2013). The liver is known as the
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main site for lipogenesis because the activity of lipogenic enzyme is substantially

higher in hepatocytes than in adipocytes (Henderson and Sargent, 1985). Basically,

cytosol is the major site for synthesis of FA even though Acetyl- CoA is generated in

the mitochondria (Saul and Smith, 2008). During the synthesis of FA, ACC a product

of malonyl CoA from Acetyl- CoA is generated from the first reaction. This reaction

is catalysed by acetyl-CoA carboxylase (ACC) and is primarily regulated by CPT1.

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PPAR signaling factors, LXR as well as SREBP-1 are some transcriptional factors

that modulates the activities of ACC. In lipogenesis, fatty acid synthesis is catalyzed

by fatty acid synthase (FASN) an important enzyme which helps in the combination

of malonyl-CoA and acetyl-CoA molecules to produce longer chain fatty acyl-CoA.

This end product of palmitoyl-CoA serve as precursor of C 16:0 (palmitic acid)

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(Henderson, 1996).

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FIG 2

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3.3 β–oxidation

The breakdown of FA which starts on the β–carbon (third carbon) is termed as FA

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oxidation. This breakdown process leads to the β–keto being cleaved between the β–
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carbon and α-carbon to produce FA deficient in two carbon atoms that can produce

acetyl CoA (Schulz, 2008). β–oxidation which is a major pathway of FA

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catabolosm/metabolism takes place in two distinct organelles in the cells;

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mitochondria as well as peroxisome through completely different enzymes (Tocher,

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2003) . According to Kompare and Rizzo (2008), the specific process of FA oxidation

has a relation with short, medium and long-chain FA which are taken in the liver and
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muscle. This is know as mitochondrial β–oxidation. It is usually activated to their

coenzyme A (CoA) esters via the breakdown of long-chain acyl-CoA synthetase

(ACL). Acyl-CoA dehydrogenase, 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA

dehydrogenase and 3-ketoacyl-CoA thiolase are the enzymes needed for each cycle of

mitochondrial β–oxidation. With the exception of Acyl-CoA dehydrogenase, the rest

are made up of mitochondrial functional protein. Mitochondrial ß-oxidation is the

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major energy producing pathway providing an important source of energy for the

heart and for skeletal muscle.

With respect to peroxisomal β–oxidation, methyl-branched carboxylic acids,

prostaglandings, dicarboxylic acids, very long-chain FA are the needed substrates.

Others include, leukotrines, isoprenoid-derived soluble vitamins, xenobiotic

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compounds as well pristanic acids (Olivares-Rubio and Vega-Lopez, 2016).

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PPAR is the main transcriptional factor that regulates β-oxidation. It also essential in

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the regulation of genes that participate in fatty acid oxidation, for instance, the cpt1a

(Van der Lei et al., 2007; Yan et al., 2015). The processes involved in the biosynthesis
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of lipids is shown in Fig 3 as described previously by Navarro–Guillén et al (2014).
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FIG 3

3.4 Transport of lipids/fatty acids

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Lipoproteins regulate the transport of endogenous and dietary lipids to peripheral

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tissues in fish (Sheridan, 1988; Tocher, 2003). Lipid transport in fish is essential as it
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plays vital roles in energy balance as well as lipid homeostasis. In addition to this, it
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plays essential role in regulation of lipid deposition in tissues. Released fatty acids
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(FA) are later taken up and re-esterified into triacylglycerols (TAG) and PL in the

endoplasmatic reticulum of enterocytes. To be transported in the blood, lipids are

assembled into lipoproteins, macromolecular complexes formed by specific carrier

proteins, apolipoproteins, with varying amounts of PL, cholesterol esters, and TAG. It

is worth noting that the intracellular transport of FA is generally performed by Fatty

Acid Binding Proteins (FABP) (Schulz, 2008).

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4.0 Effects of different lipid sources on gene expression of lipid metabolis m

related genes

Over the past few years, the aquaculture industry has seen the cry for alternative lipid

sources in fish feeds. This is because, the traditionally used fish oil in fish feed is not

sustainable and is limited and finite resource and supply cannot meet future demand

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(Betancor et al., 2016). This problem has called for research to find better alternatives

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that are easy to produce, economically viable and rich in essential fatty acids (NRC

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2011).

The proposed lipid sources includes plant oil or vegetable oil sources such as corn oil,
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palm oil, coconut oil, rapeseed oil, canola oil as well as sunflower oil. Also, oils of
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animal origin such as beef tallow and lard have been stud ied and documented to be

suitable alternatives. However, these oils have different fatty acid content hence react
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with lipid metabolism related genes differently. The different reactions occur because
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when there is a change in the lipid composition of diets, it consequently affects the
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oxidation of lipids as well as the deposition via the modulation of gene expression of

various metabolic enzymes (Price et al., 2000).

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In this section, we discuss how the various vegetable oils affect the expression of lipid

metabolism related genes.

Whereas some studies (Morais et al., 2011b; 2012; Peng et al., 2014) have

documented that substituting fish oil with vegetable oils led to upregulation of

lipogenic genes or enzymes, other studies (Panserat et al., 2008; Menoyo et al., 2004 )

have reported the contrary.

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Replacing fish oil with soybean oil seems to up-regulate some genes that are involved

in lipid metabolism. The gene expression of LPL, PPAR-𝛂, FASN as well as MTP in

the liver of juvenile turbot were up-regulated significantly when soybean meal was

increased as against fish oil (Peng et al., 2014). In this same study, LXR gene was

up-regulated when juvenile turbot (Scophthalmus maximus L.) were fed diets

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containing 33.3% soybean oil compared to their counterparts fed on diets with 66.7%

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and 100% soybean oil. Similar to this study was that of consistent Cruz-Garcia et al.,

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2009 in Atlantic salmon. These studies shows that higher dietary SO levels would

down-regulate the expression of LXR.

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Palm oil which has over the years been proven as a suitable alternative in fish feed
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was used as a substitute for FO in the diets of juvenile Nile tilapia. This led to the

alteration of some genes involved in lipid metabolism (Ayisi and Zhao, 2017). For
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instance, CPTI, ACYL, FASN as well as ACC were up-regulated. It is however not
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surprising for ACC and FASN to be both unregulated as they are known to be
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cordially regulated (Toussant et al., 1981).

Whereas feeding large yellow croacker with diets with peanut oil and rapeseed oil
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resulted in a higher relative expression of LPL than those fed other diets, fish fed

soybean oil down-regulated relative expression of LPL (Qiu et al., 2017) confirming

that lpl is an essential enzyme in the lipid catabolic metabolism (Kerner and Hoppel

2000).

Comparatively, feeding blunt snout bream (0.35g initial weight) with vegetable oils

(Soybean oil, Canola oil, peanut oil and palm oil) up-regulated the mRNA expression

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of PPAR-α and PPAR-𝛄 in the liver compared to the group fed diet rich in fish oil.

Contrary to the above studies, replacing FO with Canola oil had no significant genes

and enzymes involved in lipid metabolism at the molecular level for hepatic

transcriptional factors. This is an indication that n−3 LC-PUFA level in sea bass

cannot be modified through increased fatty acid bioconversion capacities in the liver

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(Yılmaz et al., 2016). This could probably be due to the lower ability of European

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sea bass (Dicentrarchus labrax); a marine species to synthesize EPA or DHA from

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shorter chain precursors could be due to an absence of the regulation of desaturase

and elongase activity.

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Also, the relative gene expression of fatty acyl desaturate 2 as well as fatty acid
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elongase 4 were significantly higher in fish fed three diets containing VO (WCO,

ECO and DCO) compared to fish fed diets containing FO in Gilthead Sea Bream
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(Betancor et al., 2016).

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Also, replacing dietary FO with LO significantly affected the expression of genes

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such as CPT1- α, SREBP 1 as well as PPAR-α (Stubhaug et al., 2007).

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TABLE 2

In all these studies, there seems to be differences amongst the results. These could be

attributed to factors of which include but not limited to the species and its age or size

under consideration, the duration of the feeding trial and the dietary constituents. Also

the differences in results could be attributed to the difference in sampling time post

final feeding because different mitochondrial and peroxisomal oxidation activity was

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documented at 6 and 24 hours post feeding in Sea bream (Diez et al., 2007). In

addition to the above, its worth nothing that the amount or level or lipid used affects

the expression levels of lipid related genes. Yang et al. (2016) have demonstrated t hat

feeding large yellow croacker with either low (6%), moderate (12%) or high (18%)

levels of lipid levels significantly affects the expression of genes such as LPL, LRP1,

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FASN, DGAT2, ATGL, FABP3 and FABP11. Also, there was an up-regulation of

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genes when blunt snout bream was fed higher levels of lipid (Li et al., 2013).

3. Conclusion and recommendation/future perspective

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In conclusion, it is evident that altering dietary lipid sources in diets of cultured fish
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which intend change the dietary composition of diets affects the lipid metabolic

pathways. This is because unlike vegetable oils, fish oil are known affects numerous
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enzymes and transcription factors thereby promoting β–oxidation. The differences in

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the regulation of lipid metabolism related genes is primarily due to the difference in
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experimental diets used in researches. From this study we recommend that much more

studies be conducted in order to fully understand the metabolism of lipids especially

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in the liver which is a main site for fatty acid metabolism.

Also, the difference in species is a factor leading to difference in reports. This is

because effects of vegetable oils on lipogenic and lipolytic enzymes have been

reported to differ with respect to species indicating that different vegetable oils may

have different effects on fish metabolism and that different species respond in

different ways.

18
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Acknowledgement

This work was financially supported by the China Agriculture Research System

(CARS-46) and Shanghai Collaborate Innovation Center for Aq uatic Animal Genetics

and Breeding (ZF1206) to J L Zhao.

Author contributions

PT
C.L.A conceived the idea and designed and wrote the initial manuscript in

RI
consultation with J- L Zhao. C. Yamei generated the figures. J- L Zhao supervised the

SC
entire study. All authors approved manuscript.

Conflict of interest
NU
The authors declare no conflicts of interest.
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Abbreviations

ACC Acetyl-CoA carboxylase

ACC Acetyl-CoA carboxylase

ATGL Adipose triacylglyceride lipase

CM Chylomicron

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CO Canola oil

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CPT Carnitine palmitoyltransferase

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ELOVL Elongation of very long chain fatty acids

FABP Fatty acid binding protein

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FAS Fatty acid synthase
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FO Fish oil

HDL High density lipoprotein

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HSL Hormone-sensitive lipase (HSL)

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LC-PUFA Long chain Poly unsaturated fatty acids

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LO Linseed oil

LPL Lipoprotein lipase

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ME Malic enzyme

mRNA Messenger Ribonucleic Acid

MUFA Monounsaturated fatty acid

NADPH Nicotinamide adenine dinucleotide phosphate

PeO Peanut oil

PO Palm oil

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PPAR Peroxisome proliferator-activated receptor

PUFA Poly unsaturated fatty acids

SCD Stearoyl-CoA desaturase

SFA Saturated fatty acid

SO Soybean oil

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VLDL Very low-density lipoprotein

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VO Vegetable oil

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Table 1 Compilation of enzymes, genes and transcriptional factors involved in

lipid/fatty acid metabolism

Enzymes/ Genes/Transcriptional factors Abbreviation Function in
metabolism of lipid
Peroxisome proliferator-activated receptor PPAR Transcription factor
Retinoid X receptor gamma variant a RXR Transcription factor
Extracellular signal-regulated kinases ERK Transcription factor
REDD1—mTOR1 repressor REDD1 Transcription factor

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A serine/threonine-specific protein kinase AKT2 Transcription factor
2/β

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Sterol regulatory element binding protein SREBP Transcription factor
Malic enzyme ME Production of NADPH

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Fatty acid binding protein FABP Fatty acid transport
Fatty acid translocase/cluster of FAT/CD36 Uptake of Fatty acid
differentiation 36
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Lipoprotein lipase LPL Uptake of Fatty acid
Apolipoprotein APO Fatty acid transport
Microsomal triacylglycerol transfer protein MTP Fatty acid transport
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Glucose 6-phosphate dehydrogenase G6PD Fatty acid transport

6-phosphogluconate dehydrogenase 6GPD Fatty acid transport
Acetyl-CoA Oxidase ACO β-oxidation
Acyl-CoA dehydrogenase, very long chain ACDHVL β-oxidation
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Enoyl-CoA, hydratase/Peroxisomal EHHADH β-oxidation

bifunctional enzyme
β-oxidation
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Medium-chain specific acyl-CoA ACDHM

dehydrogenase
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Acyl CoA DeHydrogenase ACDH β-oxidation

Acetyl-CoA acyltransferase 2 (thiolase) ACAT2 β-oxidation
β-oxidation
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Carnitine Palmitoyltransferase a CPT1

Mitochondrial carnitine CPT2 β-oxidation
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palmitoyltransferase I alpha1a
Monoacylglycerol lipase ABHD12 MAGL Lipolysis
Elongases of very long-chain fatty acids ELOVL Elongation
Liver X receptor LXR Lipogenesis
Fatty acid synthase FASN Fatty acid synthesis
Acetyl-CoA carboxylase ACC Fatty acid synthesis
Steroyl-CoA desaturase (delta-9 desaturase) SCD1 Fatty acid synthesis
1-acyl-sn-glycerol-3-phosphate AGPAT2 Fatty acid synthesis
yltransferase beta
Lysophospholipidacyltransferase 5 LPCAT5 Fatty acid synthesis
Ethanolaminephosphate PCYT2 Fatty acid synthesis
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cytidylyltransferase 2
Phosphatidylserine decarboxylase PISD Fatty acid synthesis
Hosphatidylserinesynthase 1 PTDSS1 Fatty acid synthesis
CDP-diacylglycerol-serine PSS Fatty acid synthesis
O-phosphatidyltransferase
Lipid LPPR1 Fatty acid synthesis
hosphatephosphatase-relatedproteintype 1
ATP citrate lyase ACYL Fatty acid synthesis
Glycerol-3-phosphate acyltransferase GPAT Synthesis of TAG

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Hormone sensitive lipid HSL Synthesis of TAG
Fatty acid desaturate FAD Fatty acid desaturation

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Table 2 Selected studies of lipid metabolism related gene expression in relation to FO

replacement with VOs in cultured species.

Species VOs Initial Li pi d Nutri tional (VO) Reference
weight metabolism regulation
(g) related genes
M. SO, CO, 0.35 PPAR-𝛂 and + by dietary Li et al., 2016
amblycephala PeO, PO PPAR-𝛄 Vegetable o il
inclusion

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P. crocea R. SO 243.52 PPAR-𝛄 + by dietary Wang et al.,
Vegetable o il 2012

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inclusion
S. maximus L SO 5.88 CPTI and LXR - by d ietary Peng et al.,

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Vegetable o il 2014
inclusion
N. tilapia PO 6.72 FASN, A CC, + by dietary Ayisi and
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SCD1 and ACYL Vegetable o il Zhao., 2017
inclusion
O. mykiss LO+S 36.5 CPT1 and ACO + by dietary Vestergen et
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Vegetable o il al., 2013

inclusion
S. maximus L. LO 5.0 FADS + by dietary Wang et al.,
Vegetable o il 2016
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inclusion
S. maximus L. LO 5.0 CPTI 𝛂 - by d ietary Wang et al.,
Vegetable o il 2016
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inclusion
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S. salar L. RO 0.142(kg) FAD, PPAR 𝛂 + by dietary Jordal et al.,

Vegetable o il 2005
inclusion
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Fig 1 Lipolysis mechanism in fish

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Fig 2 Lipogenesis mechanism in fish

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Fig 3. Biosynthesis pathway of LC-PUFA with some enzymes involved. Blue arrows
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denote Sprecher pathway (Voss et al., 1991). Figure re-drawn from Navarro–Guillén
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et al (2014).
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Highlights

 Lipid metabolism and deposition include processes such as lipogenesis, β- oxidation and
biosynthesis of long- chain PUFA
 Factors such as fish species, duration of feeding trial and dietary constituents affect
expression patterns of genes
 Altering dietary lipids affects lipid metabolism pathways
 PPAR, ACC, SCD, FAS, CPT, ACYL and ELOVL regulates lipid metabolism in fish

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