liver lipid metabolism

OR IGINAL AR TIC LE

Liver lipid metabolismP. Nguyen1, V. Leray1, M. Diez2, S. Serisier1, J. Le Bloc’h1, B. Siliart1 and H. Dumon1

1 Nutrition and Endocrinology Unit, National Veterinary School of Nantes, Nantes, France, and

2 Nutrition Unit, Faculty of Veterinary Medicine, University of Liege, Liege, Belgium

Lipid metabolism involves several pathways that are

at least in part, inter-dependent and ‘cross-regu-

lated’. There are therefore different possible

approaches to review this topic to get an overview.

The focus of the present discussion will be fatty acids

and triacylglycerols. Fatty acids are the most com-

monly stored and circulating forms of energy, and

triacylglycerols are the most common non-toxic form

of fatty acids. Fatty acids/triacylglycerols may origi-

nate from four sources (pool input): De novo lipogen-

esis, cytoplasmic triacylglycerol stores, fatty acids

derived from triacylglycerols of lipoprotein remnants

directly taken up by the liver, and plasma non-ester-

ified fatty acids (NEFA) released by adipose tissue.

The relative importance of these sources depends on

species differences (e.g. in ruminants, only modest

amounts of hepatic De novo lipogenesis occurs com-

pared with adipose tissue; the inverse is true in

birds, with liver being the main site of De novo lipo-

genesis), and on short- and long-term nutritional

status and energy balance. Fatty acids and triacylgly-

cerols may also be used in different ways (pool out-

put). Triacylglycerols may accumulate in hepatocytes

(while NEFA or activated forms of NEFA may not)

unless NEFA are oxidized (more or less completely)

or triacylglycerols are exported as constituents of

very low density lipoproteins (VLDL). Two examples

of inter-connection may be cited: (i) a low rate of

esterification when the oxidation rate is high in

response to energy demand, (ii) a strong relationship

between VLDL secretion and fatty acid/triacylglyc-

erol availability; this is especially the case in species

where De novo lipogenesis is very active, but not in

those species where high triacylglycerol concentra-

tion may be present and where the liver is not the

‘usual’ site of De novo lipogenesis.

The triacylglycerol content of hepatocytes is regu-

lated by the activity of cellular molecules that facili-

tates hepatic fatty acid uptake, fatty acid synthesis,

and esterification (‘input’) and hepatic fatty acid

Keywords

lipid metabolism, liver, ketogenesis,

lipoprotein production, nuclear factors

Correspondence

Prof. Patrick Nguyen, Unite de Nutrition et

Endocrinologie, Ecole Nationale Veterinaire de

Nantes, B.P. 40706 – F 44307 Nantes Cedex

3.Tel: 33 240687635; Fax: 33 240687746;

E-mail: [email protected]

Presented as part of the 10th Congress of the

European Society of Veterinary and

Comparative Nutrition held in Nantes, France,

October 5–7, 2006.

Received: 10 April 2007;

accepted: 26 July 2007

Summary

The liver plays a key role in lipid metabolism. Depending on species it

is, more or less, the hub of fatty acid synthesis and lipid circulation

through lipoprotein synthesis. Eventually the accumulation of lipid dro-

plets into the hepatocytes results in hepatic steatosis, which may

develop as a consequence of multiple dysfunctions such as alterations

in b-oxidation, very low density lipoprotein secretion, and pathways

involved in the synthesis of fatty acids. In addition an increased circulat-

ing pool of non-esterified fatty acid may also to be a major determinant

in the pathogenesis fatty liver disease. This review also focuses on tran-

scription factors such as sterol-regulatory-element-binding protein-1c

and peroxisome proliferator-activated receptor alpha, which promote

either hepatic fatty acid synthesis or oxidation.

DOI: 10.1111/j.1439-0396.2007.00752.x

272 Journal of Animal Physiology and Animal Nutrition 92 (2008) 272–283 ª 2008 The Authors. Journal compilation ª 2008 Blackwell Publishing Ltd

oxidation and triacylglycerol export (‘output’)

(Fig. 1). Moreover, and interestingly, fatty acids reg-

ulate overall lipid metabolism by binding nuclear

receptors that modulate gene transcription.

Fatty acid uptake and synthesis and glycerolipid

synthesis

Fatty acid uptake

Non-esterified fatty acids can arise from the hydroly-

sis of complex lipids by lipases, or the hydrolysis of

fatty acid-CoA by thioesterases. The liver takes up

NEFA from the blood in proportion to their concen-

tration. Non-esterified fatty acids enter cells via

transporters [fatty acid transport protein (FATP) or

fatty acid translocase (FAT), CD36] or diffusion.

Within the hepatocytes, long-chain fatty acids of 14

carbons or more are covalently bound and activated

by fatty acid binding protein (FABP) or acyl-CoA

synthetases (ACS) found in the microsomes and

outer mitochondrial membrane (Fig. 1). Several iso-

forms of ACS have been identified and the further

fate of a particular acyl-CoA (especially channeling

towards complex lipid synthesis and storage, or

toward oxidation) depends on which of the isoforms

catalyzes its synthesis (Coleman et al., 2002). Non-

esterified fatty acids and fatty acyl-CoA are bound to

FABP and acyl CoA binding protein which transport

them to intracellular compartments (for metabolism)

or the nucleus (to interact with transcription fac-

tors). Cells challenged with exogenous fatty acids

rapidly assimilate the fatty acids into neutral and

polar lipids, and some are oxidized. The result of

these metabolic pathways is to keep intracellular

NEFA and fatty acyl-CoA very low.

De novo synthesis of fatty acids

De novo lipogenesis (i.e., De novo synthesis of fatty

acids) is a key metabolic pathway for energy homeo-

stasis in higher animals. Lipogenic flux is tightly con-

trolled by hormonal and nutritional conditions.

Briefly, high carbohydrate diets induce, whereas

fasting or fat feeding inhibit, De novo lipogenesis; this

is especially dependent on insulin concentration,

and tissue insulin sensitivity.

Two major tissues produce fatty acids in the body:

the liver and the adipose tissue. Fatty acids synthe-

sized in the liver are exported through lipoprotein

production, and thus provide an energy source and

structural components for membrane building. In

adipose tissue, De novo synthesis of fatty acids

directly contributes to in situ fat deposition and long-

term energy storage.

De novo synthesis of fatty acids occurs in the cyto-

sol as the sequential extension of an alkanoic chain,

two carbons at a time in which acetyl units (derived

from either glucose or acetate) are added succes-

sively to a ‘primer’ (initial starting molecule, usually

acetyl-CoA), by a series of decarboxylative condensa-

tion reactions. This can be summarized by the

equation:

Fig. 1 Trans-membrane fatty acid transport,

fatty acid intracellular activation and main

pathways of activated fatty acids that may

explain intracellular triacylglycerol accumula-

tion. FA, fatty acid; FATP, FA transport pro-

tein; FAT, FA translocase; ACS, acyl-coenzyme

A synthase, NEFA, non-esterified FA; FABP, FA

binding protein; ACBP, acyl-coenzyme A bind-

ing protein; MTP, microsomal triglyceride

transfer protein; TAG, triacyglycerol.

P. Nguyen et al. Liver lipid metabolism

Journal of Animal Physiology and Animal Nutrition. ª 2008 The Authors. Journal compilation ª 2008 Blackwell Publishing Ltd 273

Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 Hþ

! Palmiticacidþ 7CO2þ8CoA þ 14NADPþþ6H2O

The rate-limiting step in this pathway is catalyzed

by acetyl-CoA carboxylase that converts acetyl-CoA

to malonyl-CoA and is considered to be the chain

extender substrate (‘donor’ of acetyl units) in the

elongation process (Kim, 1997). Formation of a new

C–C bond by condensation of the acetyl and malonyl

moieties is coupled with an energetically favourable

decarboxylation, so that the carbon originating from

CO2 introduced in the reaction catalyzed by acetyl-

CoA carboxylase is recycled. The b-ketoacyl formed

is reduced and then participates in a second round

of condensation with a malonyl moiety.

A close relationship exists between the rate of

fatty acid synthesis and the activity of fatty acid syn-

thase (FAS) (Fig. 2), a key multifunctional enzyme

that catalyzes the entire pathway of palmitate syn-

thesis (Smith et al., 2003). Fatty acid synthase is

expressed in the two major sites of fatty acid produc-

tion in the body, liver and adipose tissue, but the

relative contribution of these sites to De novo

lipogenesis is highly variable among species. Adipose

tissue is the main site of De novo lipogenesis in

non-lactating ruminants (Travers et al., 1997), pigs

(O’Hea and Leveille, 1969), dogs (Stangassinger

et al., 1986) and cats (Richard et al., 1989). In poul-

try (Leveille et al., 1975), similarly to humans (Patel

et al., 1975), the liver is the major site of De novo

lipogenesis, while in rodents and rabbits both liver

and adipose tissue are important (Pullen et al.,

1990). The mammary gland of ruminant animals

also actively synthesizes fatty acids (Bergen and

Mersmann, 2005).

The regulation of FAS by hormones (insulin, glu-

cagon) (Sul et al., 2000) and nutritional state (carbo-

hydrates and polyunsaturated fatty acids) (Volpe and

Vagelos, 1974; Clarke and Jump, 1996) has been

described in liver and adipocytes. Insulin and sub-

strate (citrate, isocitrate) availability activates the

enzyme whereas glucagon and catecholamines inhi-

bit its activity [via 3¢,5¢-cyclic adenosine monophos-

phate (cAMP)-dependent phosphorylation].

Increased concentration of fatty acyl-CoA in the

cytosol also inhibits the acetyl-CoA carboxylation.

Regulation of FAS is also largely determined by

intracellular fatty acid concentration, an increase of

which lowers FAS activity (Hillgartner et al., 1995;

Wiegman et al., 2003). The regulation of lipogenic

gene expression by insulin and fatty acids is mainly

mediated by transcription factors, such as sterol reg-

ulatory element binding proteins SREBPs (Kim et al.,

2002), and in part by nuclear receptors such as liver

Fig. 2 Main steps of fatty acid oxidation and fatty acid synthesis. These two pathways are mainly regulated (and cross-regulated) by PPARa and

LXR/SREBP, respectively, dependent on activation or inactivation by fatty acid binding. The main mitochondrial pathways are b-oxidation, the TCA

cycle and ketogenesis; in the cytosol, the main pathways are fatty acid and cholesterol synthesis; while at the cytosolic face of microsomal mem-

branes, glycerolipid synthesis occurs. CPT I, carnitine palmitoyltransferase I; CPT II, carnitine palmitoyltransferase II; TCA cycle, tricarboxylic acid

cycle; mHMG-CoA-synthase, mitochondrial hydroxymethylglutaryl-coenzyme A synthase; cHMG-CoA synthase, cytosolic HMG-CoA synthase.

Liver lipid metabolism P. Nguyen et al.

274 Journal of Animal Physiology and Animal Nutrition. ª 2008 The Authors. Journal compilation ª 2008 Blackwell Publishing Ltd

X receptors (LXRs) (Yamamoto et al., 2007). Over-

expression of SREBP-1a markedly increases the

expression of genes involved in cholesterol synthesis

and FAS, and causes a corresponding accumulation

of both cholesterol and triacylglycerals. Overexpres-

sion of hepatic SREBP-1c causes only a selective

induction of lipogenic genes, with no effect on cho-

lesterol synthesis genes (Eberle et al., 2004). The

expression of SREBP-1 is increased by insulin, and

decreased by glucagon or cAMP. Sterol regulatory

element binding proteins-1c would play a direct role

in the relative level of FAS protein between tissues

and species. Sterol regulatory element binding pro-

teins-1c and FAS genes are both expressed and cor-

related in tissues that synthesize fatty acids De novo.

In pigs, birds and rabbits, there is a close relationship

between the tissue (adipose tissue vs. liver) specific-

ity of FAS expression, protein content or activity,

and the expression of SREBP-1 mRNA. In chicken

liver, SREBP-1c and FAS transcripts and proteins are

elevated co-ordinately, whereas in pigs, SREBP-1c

and FAS transcripts and De novo lipogenesis are ele-

vated in adipose tissue (Gondret et al., 2001).

De novo lipogenesis also needs the hydrogen

donor, reduced form of nicotinamide adenine dinu-

cleotide phosphate (NADPH), which is generated

through the metabolism of glucose in the pentose

phosphate pathway and in the malic enzyme reac-

tion. In ruminants, cytosolic isocitrate dehydro-

genase can generate over 50% of the required

NADPH, the remainder being derived from the pen-

tose phosphate pathway.

Glycerolipid synthesis

The enzymes necessary for glycerolipid biosynthesis

are found in the microsomal fraction of cells. Acyl

chains from acyl-CoA are transferred consecutively

to glycerol-3-phosphate produced either via glycoly-

sis (glyceroneogenesis) or through phosphorylation

of glycerol released from adipose tissue during

lipolysis (Reshef et al., 2003). The enzymes glycero-

phosphate acyltransferase (GPAT), lysophosphatidate

acyltransferase and diacylglycerol acyltransferase

transfer acyl moieties respectively to glycerol-3-phos-

phate then subsequent compounds, leading succes-

sively to formation of 1-acylglycerol-3-phosphate

(lysophosphatidate), diacylglycerol and triacylglycer-

ols. These enzymes may be regulatory steps for

triacylglycerol synthesis, and accumulation of triacyl-

glycerols in the liver (Coleman and Lee, 2004).

Few NEFA are found in the animal body, most are

esterified to glycerol which occurs as glycerolipids.

Esterification takes place at the cytosolic face of the

microsomal membrane. Phospholipids are transferred

to membranes whereas triacylglycerols are temporar-

ily transferred to a cytosolic storage pool from which

they can be mobilized through a lipolysis/re-esterifi-

cation process (Gibbons et al., 2000). Results from

liver slice studies have suggested that species with

limited hepatic lipogenesis have less ability to secrete

triacylglycerol from the liver compared with species

in which the liver is a major or moderate source of

lipogenesis (Pullen et al., 1990). Fatty acids could

preferentially be esterified into phospholipids that

would be incorporated into membranes, then trans-

ferred to pre-high-density lipoprotein particles

(Yokoyama, 2006). Nevertheless even in such cases,

the liver can also actively synthesize triacylglycerols

when high concentrations of NEFA are present and

phospholipid transfer to membranes is overloaded.

The first enzyme involved is GPAT, which is regu-

lated (via dephosphorylation and phosphorylation)

by 5¢-phosphates of adenosine (AMP)-activated

kinase (AMPK), a sensor of cellular energy supply.

5¢-phosphates of adenosine kinase is activated when

cellular 5¢(pyro)-triphosphates of adenosine (ATP)

concentration is relatively depleted and AMP levels

rise. 5¢-phosphates of adenosine kinase stimulates

fatty acid oxidation and inhibits several synthetic

pathways including those of cholesterol, glycogen

and fatty acids. The action of AMPK regulates acyl-

CoA channeling towards b-oxidation and away from

glycerolipid biosynthesis. 5¢-phosphates of adenosine

kinase phosphorylates and downregulates acetyl-

CoA carboxylase, thereby decreasing the production

of malonyl-CoA. Without inhibition by malonyl-

CoA, the activity of carnitine palmitoyltransferase-1

(CPT-1), the rate-controlling step in b-oxidation

increases, as does fatty acid oxidation. Thus, when

cellular fuel supplies are low, AMPK increases the

flux of acyl-CoA into the pathway of b-oxidation

while simultaneously inhibiting GPAT activity and

triacylglycerol synthesis. Conversely SREBP-1c

responds to high fuel supplies and when it is overex-

pressed, the expression of genes such as FAS or

GPAT increases (Pegorier et al., 2004).

Overall, triacylglycerol synthesis is under the con-

trol of transcription factors and nuclear receptors

such as SREBP-1c, carbohydrate regulatory element

binding protein (ChREBP) (Dentin et al., 2006), per-

oxisome proliferator-activated receptor c (PPARc)

and LXRs and their ligands. These play an important

role alongside hormonal and nutritional regulators,

such as insulin, carbohydrate, and fatty acids (Coleman

and Lee, 2004).



Fatty acid oxidation

Non-esterified acyl-CoA may be oxidized, either in

the mitochondria or peroxisomes. Mitochondrial

oxidation may be either complete or incomplete.

Incomplete oxidation leads to formation of ketone

bodies (Fig. 3).

The two main factors regulating the degree to

which fatty acids are oxidized by the liver are the

supply of fatty acids to the liver (via lipolysis), and

the partitioning between oxidation and microsomal

esterification.

Intramitochondrial oxidation

Intramitochondrial oxidation of fatty acyl-CoA

occurs through the b-oxidation pathways resulting

in the formation of acetyl-CoA. During this process,

electrons are transferred to flavin-adenine dinucleo-

tide (FAD) and oxidized form of nicotinamide-

adenine dinucleotide (NAD+), forming the reduced

forms of these coenzymes, which in turn donate

electrons to the electron transport chain to drive

ATP synthesis. The acetyl-CoA can be oxidized com-

pletely to carbon dioxide in the tricarboxylic acid

cycle (TCA).

The mitochondrial matrix does not contain any

ACS enzyme that could activate fatty acids with

14 carbons or more. Entry of these long-chain

fatty acids into the mitochondria is regulated by

the activity of the enzyme CPT-I (Kerner and Hop-

pel, 2000). This enzyme is an integral protein of

the outer mitochondrial membrane, and catalyzes

the formation of acyl-carnitine molecules which

are transported across the mitochondrial membrane

by a specific carrier protein and are reconverted to

acyl-CoA within the mitochondrial matrix by the

action of CPT-II, a peripheral protein of the inner

mitochondrial membrane. Short- and medium-

chain fatty acids (12 carbons or less) pass through

the mitochondrial membrane and are activated by

ACS within the mitochondrial matrix. Conse-

quently, oxidation of these fatty acids is not con-

trolled by CPT-I.

The activity of CPT-I is inhibited by interaction

with malonyl-CoA, the product of the first step of

De novo synthesis of fatty acids catalyzed by acetyl-

CoA carboxylase (the activity of which is stimulated

by insulin) (Brindle et al., 1985). Negative energy

balance results in a decrease in malonyl-CoA, and

an increase in fatty acid oxidation. The control of

CPT-I by malonyl-CoA would be a way to prevent

simultaneous oxidation and synthesis of fatty acids

within the liver cell, a potential futile cycle. In rumi-

nants, CPT-I also is highly sensitive to inhibition by

methylmalonyl-CoA which is an intermediate in the

conversion of propionate to succinyl-CoA in the

process of gluconeogenesis.

Fig. 3 Fatty acid oxidation: main steps of mitochondrial and peroxisomal b-oxidation, and fate of acetyl-CoenzymeA.



Peroxisomal and microsomal oxidation

Whereas they function similarly (b-oxidation), there

are notable differences between the peroxisomal

and mitochondrial pathways for fatty acid oxidation.

Peroxisomal b-oxidation is responsible for the

metabolism of very long chain fatty acids while

mitochondrial b-oxidation is responsible for the oxi-

dation of short, medium and long chain fatty acids.

In peroxisomes, the first dehydrogenation of mito-

chondrial b-oxidation is replaced with an oxidation

(acyl-CoA oxidase), resulting in the formation of

H2O2 rather than reduced NAD+. Secondly, peroxi-

somes do not contain an electron transport chain.

Peroxisomal b-oxidation therefore results in less

ATP-energy than does mitochondrial b-oxidation.

Peroxisomal b-oxidation is active with long-chain

fatty acids (that are relatively poor substrates for

mitochondrial b-oxidation) and provides an ‘over-

flow’ pathway to help cope with high availability of

fatty acids. There are nevertheless wide differences

between species. For example, peroxisomal oxidation

in liver homogenates from cows may represent 50%

and 77% of the total capacity for the initial cycle of

b-oxidation of palmitate and octanoate, respectively,

but only 26% and 65% for rats (Grum et al., 1994).

Very long chain fatty acids are also metabolized

by the cytochrome P450 CYP4A x-oxidation system

to dicarboxylic acids. Indeed, the CYP4A enzymes

are especially capable of hydroxylating the terminal

x-carbon and, to a lesser extent the (x-1) position

of fatty acids. W-hydroxylation is followed by cyto-

solic oxidation to produce long chain dicarboxylic

acids (Simpson, 1997). These acids cannot be readily

metabolized by the mitochondria, whereas they are

the preferred substrate for the peroxisomal b-oxida-

tion pathway. They are thus taken up by the per-

oxisomes and oxidized to fatty acids, which can

then be shortened even further by the mitochon-

dria. The induction of this system would be an

adaptive response by the hepatocyte to maintain

cellular lipid homeostasis. It is important during

fatty acid overload of the mitochondrial b-oxidation

system with the microsomal CYP4A-mediated x-oxi-

dation and peroxisomal b-oxidation being co-opera-

tively regulated to achieve fatty acid metabolism in

the liver.

Ketogenesis

Under conditions of increased fatty acid uptake, the

liver often produces large amounts of the ketone

bodies, acetoacetate and b-hydroxybutyrate, in a

process known as ketogenesis. Ketogenesis is

enhanced in times of increased NEFA uptake by the

liver, when low insulin levels cause activation of

CPT-I, allowing extensive uptake of fatty acids into

mitochondria.

Conversion of acetyl-CoA to ketone bodies, rather

than complete oxidation in the TCA cycle, results in

the formation of less ATP/mole of fatty acid oxidized

(e. g. five times less in the case of palmitate: 129 vs.

27 ATP/mole, TCA and oxidative phosphorylation in

the electron transport chain vs. conversion of acetyl-

CoA to ketone bodies). Ketogenesis therefore allows

the liver to metabolize about five times more fatty

acids (for the same ATP yield), and conversion of

fatty acids into water-soluble fuels may be an impor-

tant short-term strategy to redistribute energy.

Ketogenesis (as well as cholesterol biosynthesis) is

controlled indirectly by CPT-I (McGarry et al., 1989)

and directly by the activity of the mitochondrial key

regulatory enzyme 3-hydroxy-3-methylglutaryl-CoA

(HMG-CoA) synthase (Hegardt, 1999). The enzyme

is regulated by two systems: succinylation in the

short term, and transcriptional regulation in the long

term (prolonged energy deficit). When the succinyl-

CoA pool size increases as a result of an increased

flux of glucogenic metabolites, a succinyl group is

added to a regulatory sub-unit of HMG-CoA syn-

thase, which inactivates the enzyme. Both control

mechanisms are influenced by nutritional and hor-

monal factors, which explain the incidence of keto-

genesis.

Triacylglycerol export (VLDL synthesis and

secretion)

The mechanism for synthesis and secretion of VLDL

from liver is well known (Adeli et al., 2001). Apo-

protein B100 (apoB100; and apoB48 in a few spe-

cies) is the key component whose rate of synthesis

in the rough endoplasmic reticulum controls the

overall rate of VLDL production. Lipid components

that are synthesized in the smooth endoplasmic

reticulum are added by the microsomal triacylglyc-

erol transfer protein to apoprotein B (White et al.,

1998) as it moves to the junction of the two com-

partments. After being carried to the Golgi apparatus

in transport vesicles, the apoproteins are glycosylat-

ed. Secretory vesicles bud off the Golgi membrane,

migrate to the sinusoıdal membrane of the hepato-

cyte, then fuse with the membrane and release the

VLDL into blood.

Animal models have shown that the availability of

fatty acids is not the only or the major determinant



of the rate of VLDL production (Kendrick et al.,

1998; Mason, 1998). Where the limitation in VLDL

synthesis or secretion resides is unknown. The rate

of synthesis or assembly would be more likely to be

limiting than the secretory process per se (White

et al., 1998). Inhibition of microsomal triacylglycerol

transfer protein (evaluated in the treatment of ath-

erosclerosis) blocks the assembly and secretion of

VLDL and chylomicrons but leads to steatosis at least

in mice (Liao et al., 2003). Possible limitations also

include a high rate of degradation of apoB100,

or deficient synthesis of phosphatidylcholine or

cholesterol.

There are important species differences in the abil-

ity to export triacylglycerols from the liver as VLDL

despite similar rates of esterification of fatty acids to

triacylglycerols. It has been suggested that among

different species, the rate of export of triacylglycerols

from the liver is proportional to the capacity of

De novo fatty acid synthesis. Cattle (Grummer, 1993),

goat (Kleppe et al., 1988) and pigs that do not syn-

thesize fatty acids in the liver also have low rates of

triacylglycerol export, whereas poultry that actively

synthesize fatty acids in the liver secrete VLDL at

very high rates (Pullen et al., 1990). Rates of VLDL

export are intermediate for rats and rabbits that

undertake lipogenesis in both liver and adipose tis-

sues (Pullen et al., 1990).

The origin of the fatty acids incorporated into tria-

cylglycerols can affect the rate of VLDL export. In

obese mice, De novo lipogenesis in the liver does not

stimulate VLDL output (Wiegman et al., 2003). In

rats, high carbohydrate diets enhance the hepatic

output of VLDL triacylglycerols, but this increased

secretion of triacylglycerols is accomplished by

enhanced formation of VLDL triglyceride from exog-

enous NEFA rather than from fatty acids synthesised

De novo in the liver (Schonfeld and Pfleger, 1971).

Plasma NEFA therefore seem to play an important

role in enhancing hepatic esterification and stimulat-

ing VLDL production (Julius, 2003). The situation

would be exacerbated in an insulin-resistant state,

which also promotes increased stability of nascent

apoprotein B and enhances the expression of micro-

somal triacylglycerol transfer protein (Taghibiglou

et al., 2000; Wiegman et al., 2003).

The mechanism of clearance of accumulated tria-

cylglycerols has not been fully elucidated. In rats,

triacylglycerols stored in lipid droplets do not con-

tribute directly to the synthesis of VLDL. Rather it

appears that lipolysis of stored triacylglycerol by a

microsomal lipase generates NEFA and membrane-

bound diacylglycerols, and eventually monoacylgly-

cerols. Usually, as the same lipase hydrolyzes tri-

and diacylglycerols, higher triacylglycerol availability

and affinity prevents unnecessary formation of

monoacylglycerol (Abo-Hashema et al., 1999). Dia-

cylglycerols (and eventually monoacylglycerols) are

re-esterified in the microsomal membrane (mainly

by a diacylglycerol acyltransferase, and to a lesser

extent by monoacylglycerol acyltransferase), translo-

cated into the microsomal lumen, then incorporated

into nascent VLDL (Gibbons et al., 2000).

In mice with increased De novo lipogenesis in the

liver, VLDL production can be either unaltered or

increased, probably depending on the cause of the

increase in De novo lipogenesis and the capacity of

the liver to increase fatty acid b-oxidation (Wiegman

et al., 2003). The inhibition of glucose-6-phospha-

tase results in an increase in De novo lipogenesis

without any stimulation of VLDL production (Bands-

ma et al., 2001). In contrast, hamsters with

increased De novo lipogenesis induced by fructose

have increased VLDL production. Therefore, it is

likely that different molecular mechanisms are

involved explaining the relation between steatosis

and the rate of basal VLDL production in different

conditions.

Regulation at molecular level

Fatty acids regulate gene expression by controlling

the activity or abundance of key transcription factors

(Jump et al., 2005), which at the molecular level

play a crucial role; this has been particularly illus-

trated by the link between alterations in their func-

tions and the occurrence of major metabolic

diseases. Many transcription factors have been iden-

tified as prospective targets for fatty acid regulation,

including peroxisome proliferator-activated receptors

(PPARa, b and c) (Schoonjans et al., 1996), SREBP-

1c (Xu et al., 1999), retinoid X receptor (RXRa)

(Dubuquoy et al., 2002), and LXRa (Zelcer and Ton-

tonoz, 2006). They integrate signals from various

pathways and coordinate the activity of the meta-

bolic machinery necessary for fatty acid metabolism

with the supply of energy and fatty acids.

Nuclear receptors and transcription factors

Retinoid X receptors (RXRs) play an important regu-

latory role in metabolic signaling pathways (glucose,

fatty acid and cholesterol metabolism) (Ahuja et al.,

2003). These receptors activate transcription as ho-

modimers or as obligate heterodimeric partners of

numerous other nuclear receptors; especially PPARs



and LXRs that belong to the nuclear receptor super-

family of ligand-activated transcription factors and

which have been implicated in diverse pathways of

lipid metabolism (Barish, 2006; Zelcer and Tontonoz,

2006). Similarly to other nuclear receptors, they

interact with nuclear proteins known as co-activa-

tors and co-repressors. Activated PPARs or LXRs

heterodimerize with RXR (PPAR-RXR or LXR-RXR

complex). The heterodimers modulate the transcrip-

tion of target genes by binding to their promoter

region on a specific DNA sequence termed the per-

oxisome proliferator responsive element (PPRE); this

consists of a direct repeat of the nuclear receptor

hexameric DNA core recognition (AGGTCA) motif

spaced by one nucleotide (Latruffe et al., 2001).

Liver X receptors bind to cognate LXR response ele-

ment (LXRE) sequences that typically consist of a

direct repeat of TGACCT spaced by four nucleotides

(Willy and Mangelsdorf, 1997). PPARs and LXRs act

as key messengers responsible for the translation of

nutritional, metabolic and pharmacological stimuli

into changes in the expression of genes, especially

those genes involved in lipid metabolism.

PPAR-a is highly expressed in the liver and in

those tissues that use a lot of lipid-derived energy,

where it regulates a set of enzymes crucial for fatty

acid oxidation. Indeed, its primary role is to increase

the cellular capacity to mobilize and catabolize fatty

acids. It increases transcription and expression of

proteins and enzymes necessary to transport and

catabolize fatty acids (FABP, FAT, CPT-I etc.). It also

participates in the regulation of mitochondrial and

peroxisomal fatty acid b-oxidation systems, micro-

somal x-oxidation system (acyl-CoA oxidase,

CYP4A1 and CYP4A6 etc.), and the production of

apolipoproteins (Everett et al., 2000). PPAR-a func-

tions as a sensor for fatty acids and ineffective PPAR-

a sensing (or PPAR-a null phenotype) can lead to

reduced energy burning, resulting in hepatic steato-

sis. The DNA-binding properties of PPARa and other

transcription factors (RXRs) on the PPRE of the

mitochondrial HMG-CoA synthase promoter have

revealed that ketogenesis can be regulated by fatty

acids. Interestingly HMG-CoA synthase can react

with PPARa and thus autoregulate its own transcrip-

tion. PPARc activation is followed by overexpression

of lipogenic enzymes (acetylCoA carboxylase, FAS,

GPAT) and FATP. Liver X receptors are master regu-

lators of whole-body cholesterol homeostasis.

CYP7a1, which is another member of the cyto-

chrome P450 enzyme family and the rate-limiting

enzyme in the pathway of bile acid synthesis is the

first direct target of LXRs. Their target genes also

include the ATP-binding cassette (ABC) subfamilies

(ABCA1 and G1: cholesterol efflux, G5 and G8: bile

acid excretion and intestinal cholesterol absorption).

In addition to their role in cholesterol metabolism,

LXRs are also key regulators of hepatic lipogenesis

through the upregulation of the master regulator of

hepatic lipogenesis, SREBP-1c, as well as induction

of FAS and acyl-CoA carboxylase (Zelcer and Tonto-

noz, 2006). Sterol regulatory element binding pro-

teins-1 has also been identified as a potent activator

of lipogenic gene expression. The regulation of its

gene expression by dietary and hormonal factors has

already been mentioned. Moreover, polyunsaturated

fatty acids suppress SREBP-1c gene expression and

inhibit SREBP-1c protein maturation, which results

in suppression of its target genes (such as FAS and

GPAT) resulting in reduced fatty acid and triglyceride

synthesis (Kim et al., 2002).

Nuclear factors and Gene regulation

Nuclear factors play a crucial role in the regulation

of lipid metabolism. Indeed, fatty acid metabolism is

transcriptionally regulated by two main systems

under the control of either LXRs or PPARs. Liver X

receptors activate expression of SREBP-1c, an

already mentioned dominant lipogenic gene regula-

tor, whereas genes encoding peroxisomal, micro-

somal and some mitochondrial fatty acid

metabolizing enzymes in the liver are transcription-

ally regulated by PPARa. An intricate network of

nutritional transcription factors with mutual interac-

tions has been proposed, resulting in efficient reci-

procal regulation of lipid degradation and

lipogenesis. LXR activation, either by overexpression

of LXR or its ligand would cause suppression of

PPARa signaling, by RXRa competition between

PPAR and LXR (Ide et al., 2003). Reciprocally,

PPARa activation would suppress the LXR-SREBP-1c

pathway through reduction of LXR/RXRa formation

(Yoshikawa et al., 2003). As LXRa and PPARa regu-

late alternate pathways of fatty acid synthesis and

catabolism, these nuclear receptors would ‘cross-talk’

to ensure that antagonistic pathways are not simul-

taneously activated. Other studies have not shown

this cross-talk, but some work indicates that PPARaand LXRa activate an overlapping set of genes

involved in both fatty acid catabolism and synthesis

(Anderson et al., 2004). Hepatic peroxisomal fatty

acid b-oxidation would especially be regulated by

LXRa, and this process might serve as a counterregu-

latory mechanism for responding to extreme situa-

tions such as hypertriglyceridaemia and liver



steatosis (Hu et al., 2005). In such unusual situa-

tions, PPARc expression which is usually low in liver

(10–30% of expression in adipose tissue) would nev-

ertheless be capable of selectively upregulating a

subset of the lipogenic enzymes in hepatocytes, thus

enhancing both lipid synthesis and accumulation

leading to steatosis (Coleman and Lee, 2004). PPARchas been reported to activate LXRa gene expression

(Tsukamoto, 2005) which could in turn activate

SREBP-1c gene expression and downregulate PPARa,

leading to speculation that these four factors could

form an auto-loop controlling the activation of adi-

pogenesis and the inactivation of oxidation.

Fatty acids and Gene regulation

Receptors and transcription factors drive liver lipid

metabolism. In turn, long chain fatty acids, acyl-

CoAs, and other fatty acid-derived compounds (e.g.,

eicosanoids) are the ligands of nuclear factors and

are responsible for their activation, thus acting as

metabolic regulators of gene transcription. Fatty

acids induce changes in the activity or abundance of

at least four transcription factor families: PPARs,

LXRs, hepatic nuclear factor 4, and SREBP (Pegorier

et al., 2004; Jump et al., 2005). Long chain polyun-

saturated fatty acids are strong ligands, while mono-

unsaturated fatty acids are only weak ligands and

saturated fatty acids poor ligands. Moreover, down-

regulation of gene expression by fatty acids would

be restricted to polyunsaturated fatty acids, whereas

upregulation would be independent of the degree of

saturation (Pegorier et al., 2004). Differences might

involve differential metabolism (oxidative pathways,

kinetics etc.) and selective transport of fatty acids to

the nucleus. Table 1 shows some genes involved in

lipid metabolism whose expression is regulated by

fatty acids. An abundance of polyunsaturated fatty

acids regulates numerous PPARa target genes, espe-

cially those involved in fatty acid oxidation, while

they block the ligand-dependent activation of LXR.

Long chain (polyunsaturated) fatty acids suppress

SREBP-1c activity, leading to a reduction in liver tri-

acylglycerol content; directly by reducing the nuclear

abundance of SREBP-1c, and indirectly because of

inactivation of LXR.

In summary, hepatic lipid metabolism is a highly

co-ordinated process, in which many pathways are

regulated by nuclear receptors and transcription fac-

tors. It is under the tight control of intracellular

NEFA levels and composition, but also other meta-

bolic and hormonal factors (e.g. carbohydrate, alco-

hol, insulin). Despite the complexity and degree of

co-ordination of the liver lipid machinery, the over-

flow of any metabolite pool and/or alteration of

nuclear receptors sensing these can lead to organ

function impairment and subsequent pathologies.

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