DOI: 10.1111/j.1439-0396.2007.00752.

ORIGINAL ARTICLE

Liver lipid metabolism

P. Nguyen1, V. Leray1, M. Diez2, S. Serisier1, J. Le Bloch1, B. Siliart1 and H. Dumon1
1 Nutrition and Endocrinology Unit, National Veterinary School of Nantes, Nantes, France, and ` ge, Lie ` ge, Belgium 2 Nutrition Unit, Faculty of Veterinary Medicine, University of Lie

Keywords lipid metabolism, liver, ketogenesis, lipoprotein production, nuclear factors Correspondence de Nutrition et Prof. Patrick Nguyen, Unite te rinaire de Endocrinologie, Ecole Nationale Ve Nantes, B.P. 40706 F 44307 Nantes Cedex 3.Tel: 33 240687635; Fax: 33 240687746; E-mail: pnguyen@vet-nantes.fr Presented as part of the 10th Congress of the European Society of Veterinary and Comparative Nutrition held in Nantes, France, October 57, 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 droplets 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 circulating pool of non-esteried fatty acid may also to be a major determinant in the pathogenesis fatty liver disease. This review also focuses on transcription factors such as sterol-regulatory-element-binding protein-1c and peroxisome proliferator-activated receptor alpha, which promote either hepatic fatty acid synthesis or oxidation.

Lipid metabolism involves several pathways that are at least in part, inter-dependent and cross-regulated. 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 commonly stored and circulating forms of energy, and triacylglycerols are the most common non-toxic form of fatty acids. Fatty acids/triacylglycerols may originate from four sources (pool input): De novo lipogenesis, cytoplasmic triacylglycerol stores, fatty acids derived from triacylglycerols of lipoprotein remnants directly taken up by the liver, and plasma non-esteried 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 compared with adipose tissue; the inverse is true in birds, with liver being the main site of De novo lipogenesis), and on short- and long-term nutritional
272

status and energy balance. Fatty acids and triacylglycerols may also be used in different ways (pool output). 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 esterication when the oxidation rate is high in response to energy demand, (ii) a strong relationship between VLDL secretion and fatty acid/triacylglycerol availability; this is especially the case in species where De novo lipogenesis is very active, but not in those species where high triacylglycerol concentration may be present and where the liver is not the usual site of De novo lipogenesis. The triacylglycerol content of hepatocytes is regulated by the activity of cellular molecules that facilitates hepatic fatty acid uptake, fatty acid synthesis, and esterication (input) and hepatic fatty acid

Journal of Animal Physiology and Animal Nutrition 92 (2008) 272283 2008 The Authors. Journal compilation 2008 Blackwell Publishing Ltd

P. Nguyen et al.

Liver lipid metabolism

oxidation and triacylglycerol export (output) (Fig. 1). Moreover, and interestingly, fatty acids regulate overall lipid metabolism by binding nuclear receptors that modulate gene transcription. Fatty acid uptake and synthesis and glycerolipid synthesis
Fatty acid uptake

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

Non-esteried fatty acids can arise from the hydrolysis 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 concentration. Non-esteried 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 isoforms of ACS have been identied 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). Nonesteried 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 factors). Cells challenged with exogenous fatty acids

De novo lipogenesis (i.e., De novo synthesis of fatty acids) is a key metabolic pathway for energy homeostasis in higher animals. Lipogenic ux is tightly controlled by hormonal and nutritional conditions. Briey, 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 synthesized 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 longterm energy storage. De novo synthesis of fatty acids occurs in the cytosol 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 successively to a primer (initial starting molecule, usually acetyl-CoA), by a series of decarboxylative condensation 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 accumulation. FA, fatty acid; FATP, FA transport protein; FAT, FA translocase; ACS, acyl-coenzyme A synthase, NEFA, non-esteried FA; FABP, FA binding protein; ACBP, acyl-coenzyme A binding protein; MTP, microsomal triglyceride transfer protein; TAG, triacyglycerol.

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

273

Liver lipid metabolism

P. Nguyen et al.

Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H ! Palmiticacid 7CO2 8CoA 14NADP 6H2 O 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 CC 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 acetylCoA 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 synthase (FAS) (Fig. 2), a key multifunctional enzyme that catalyzes the entire pathway of palmitate synthesis (Smith et al., 2003). Fatty acid synthase is expressed in the two major sites of fatty acid production 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 (OHea and Leveille, 1969), dogs (Stangassinger

et al., 1986) and cats (Richard et al., 1989). In poultry (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, glucagon) (Sul et al., 2000) and nutritional state (carbohydrates and polyunsaturated fatty acids) (Volpe and Vagelos, 1974; Clarke and Jump, 1996) has been described in liver and adipocytes. Insulin and substrate (citrate, isocitrate) availability activates the enzyme whereas glucagon and catecholamines inhibit its activity [via 3,5-cyclic adenosine monophosphate (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 regulatory 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 membranes, 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.

274

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

P. Nguyen et al.

Liver lipid metabolism

X receptors (LXRs) (Yamamoto et al., 2007). Overexpression 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. Overexpression of hepatic SREBP-1c causes only a selective induction of lipogenic genes, with no effect on cholesterol 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 proteins-1c and FAS genes are both expressed and correlated 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) specicity 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 elevated in adipose tissue (Gondret et al., 2001). De novo lipogenesis also needs the hydrogen donor, reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), which is generated through the metabolism of glucose in the pentose phosphate pathway and in the malic enzyme reaction. In ruminants, cytosolic isocitrate dehydrogenase can generate over 50% of the required NADPH, the remainder being derived from the pentose 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 glycolysis (glyceroneogenesis) or through phosphorylation of glycerol released from adipose tissue during lipolysis (Reshef et al., 2003). The enzymes glycerophosphate acyltransferase (GPAT), lysophosphatidate acyltransferase and diacylglycerol acyltransferase transfer acyl moieties respectively to glycerol-3-phosphate then subsequent compounds, leading successively to formation of 1-acylglycerol-3-phosphate (lysophosphatidate), diacylglycerol and triacylglycerols. These enzymes may be regulatory steps for triacylglycerol synthesis, and accumulation of triacylglycerols in the liver (Coleman and Lee, 2004). Few NEFA are found in the animal body, most are esteried to glycerol which occurs as glycerolipids.

Esterication takes place at the cytosolic face of the microsomal membrane. Phospholipids are transferred to membranes whereas triacylglycerols are temporarily transferred to a cytosolic storage pool from which they can be mobilized through a lipolysis/re-esterication 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 esteried into phospholipids that would be incorporated into membranes, then transferred 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 rst enzyme involved is GPAT, which is regulated (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 acylCoA channeling towards b-oxidation and away from glycerolipid biosynthesis. 5-phosphates of adenosine kinase phosphorylates and downregulates acetylCoA carboxylase, thereby decreasing the production of malonyl-CoA. Without inhibition by malonylCoA, 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 ux 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 overexpressed, the expression of genes such as FAS or GPAT increases (Pegorier et al., 2004). Overall, triacylglycerol synthesis is under the control of transcription factors and nuclear receptors such as SREBP-1c, carbohydrate regulatory element binding protein (ChREBP) (Dentin et al., 2006), peroxisome 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).
275

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

Liver lipid metabolism

P. Nguyen et al.

Fatty acid oxidation Non-esteried 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 esterication.
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 avin-adenine dinucleotide (FAD) and oxidized form of nicotinamideadenine 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 completely 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 Hoppel, 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 specic 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 mediumchain fatty acids (12 carbons or less) pass through the mitochondrial membrane and are activated by ACS within the mitochondrial matrix. Consequently, oxidation of these fatty acids is not controlled by CPT-I. The activity of CPT-I is inhibited by interaction with malonyl-CoA, the product of the rst step of De novo synthesis of fatty acids catalyzed by acetylCoA 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 ruminants, 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.

276

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

P. Nguyen et al.

Liver lipid metabolism

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 oxidation of short, medium and long chain fatty acids. In peroxisomes, the rst dehydrogenation of mitochondrial b-oxidation is replaced with an oxidation (acyl-CoA oxidase), resulting in the formation of H2O2 rather than reduced NAD+. Secondly, peroxisomes 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 overow 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 cytosolic 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-oxidation pathway. They are thus taken up by the peroxisomes and oxidized to fatty acids, which can then be shortened even further by the mitochondria. 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-oxidation and peroxisomal b-oxidation being co-operatively regulated to achieve fatty acid metabolism in the liver.
Ketogenesis

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. ve times less in the case of palmitate: 129 vs. 27 ATP/mole, TCA and oxidative phosphorylation in the electron transport chain vs. conversion of acetylCoA to ketone bodies). Ketogenesis therefore allows the liver to metabolize about ve times more fatty acids (for the same ATP yield), and conversion of fatty acids into water-soluble fuels may be an important 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 decit). When the succinylCoA pool size increases as a result of an increased ux of glucogenic metabolites, a succinyl group is added to a regulatory sub-unit of HMG-CoA synthase, which inactivates the enzyme. Both control mechanisms are inuenced by nutritional and hormonal factors, which explain the incidence of ketogenesis. Triacylglycerol export (VLDL synthesis and secretion) The mechanism for synthesis and secretion of VLDL from liver is well known (Adeli et al., 2001). Apoprotein B100 (apoB100; and apoB48 in a few species) 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 triacylglycerol transfer protein to apoprotein B (White et al., 1998) as it moves to the junction of the two compartments. After being carried to the Golgi apparatus in transport vesicles, the apoproteins are glycosylated. Secretory vesicles bud off the Golgi membrane, migrate to the sinuso dal membrane of the hepatocyte, 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
277

Under conditions of increased fatty acid uptake, the liver often produces large amounts of the ketone bodies, acetoacetate and b-hydroxybutyrate, in a

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

Liver lipid metabolism

P. Nguyen et al.

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 atherosclerosis) 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 decient synthesis of phosphatidylcholine or cholesterol. There are important species differences in the ability to export triacylglycerols from the liver as VLDL despite similar rates of esterication 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 synthesize 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 tissues (Pullen et al., 1990). The origin of the fatty acids incorporated into triacylglycerols 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 exogenous NEFA rather than from fatty acids synthesised De novo in the liver (Schonfeld and Peger, 1971). Plasma NEFA therefore seem to play an important role in enhancing hepatic esterication and stimulating 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 microsomal triacylglycerol transfer protein (Taghibiglou et al., 2000; Wiegman et al., 2003). The mechanism of clearance of accumulated triacylglycerols has not been fully elucidated. In rats, triacylglycerols stored in lipid droplets do not contribute directly to the synthesis of VLDL. Rather it appears that lipolysis of stored triacylglycerol by a microsomal lipase generates NEFA and membranebound diacylglycerols, and eventually monoacylgly278

cerols. Usually, as the same lipase hydrolyzes triand diacylglycerols, higher triacylglycerol availability and afnity prevents unnecessary formation of monoacylglycerol (Abo-Hashema et al., 1999). Diacylglycerols (and eventually monoacylglycerols) are re-esteried in the microsomal membrane (mainly by a diacylglycerol acyltransferase, and to a lesser extent by monoacylglycerol acyltransferase), translocated 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-phosphatase results in an increase in De novo lipogenesis without any stimulation of VLDL production (Bandsma 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 illustrated by the link between alterations in their functions and the occurrence of major metabolic diseases. Many transcription factors have been identied as prospective targets for fatty acid regulation, including peroxisome proliferator-activated receptors (PPARa, b and c) (Schoonjans et al., 1996), SREBP1c (Xu et al., 1999), retinoid X receptor (RXRa) (Dubuquoy et al., 2002), and LXRa (Zelcer and Tontonoz, 2006). They integrate signals from various pathways and coordinate the activity of the metabolic 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 regulatory role in metabolic signaling pathways (glucose, fatty acid and cholesterol metabolism) (Ahuja et al., 2003). These receptors activate transcription as homodimers or as obligate heterodimeric partners of numerous other nuclear receptors; especially PPARs

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

P. Nguyen et al.

Liver lipid metabolism

and LXRs that belong to the nuclear receptor superfamily 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-activators and co-repressors. Activated PPARs or LXRs heterodimerize with RXR (PPAR-RXR or LXR-RXR complex). The heterodimers modulate the transcription of target genes by binding to their promoter region on a specic DNA sequence termed the peroxisome 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 element (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, microsomal x-oxidation system (acyl-CoA oxidase, CYP4A1 and CYP4A6 etc.), and the production of apolipoproteins (Everett et al., 2000). PPAR-a functions as a sensor for fatty acids and ineffective PPARa sensing (or PPAR-a null phenotype) can lead to reduced energy burning, resulting in hepatic steatosis. 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 transcription. PPARc activation is followed by overexpression of lipogenic enzymes (acetylCoA carboxylase, FAS, GPAT) and FATP. Liver X receptors are master regulators of whole-body cholesterol homeostasis. CYP7a1, which is another member of the cytochrome P450 enzyme family and the rate-limiting enzyme in the pathway of bile acid synthesis is the rst direct target of LXRs. Their target genes also

include the ATP-binding cassette (ABC) subfamilies (ABCA1 and G1: cholesterol efux, 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 Tontonoz, 2006). Sterol regulatory element binding proteins-1 has also been identied 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 regulator, whereas genes encoding peroxisomal, microsomal and some mitochondrial fatty acid metabolizing enzymes in the liver are transcriptionally regulated by PPARa. An intricate network of nutritional transcription factors with mutual interactions has been proposed, resulting in efcient reciprocal 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 regulate alternate pathways of fatty acid synthesis and catabolism, these nuclear receptors would cross-talk to ensure that antagonistic pathways are not simultaneously activated. Other studies have not shown this cross-talk, but some work indicates that PPARa and 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 counterregulatory mechanism for responding to extreme situations such as hypertriglyceridaemia and liver
279

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

Liver lipid metabolism

P. Nguyen et al.

steatosis (Hu et al., 2005). In such unusual situations, PPARc expression which is usually low in liver (1030% of expression in adipose tissue) would nevertheless 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). PPARc has 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 adipogenesis and the inactivation of oxidation.
Fatty acids and Gene regulation

Receptors and transcription factors drive liver lipid metabolism. In turn, long chain fatty acids, acylCoAs, 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 polyunsaturated fatty acids are strong ligands, while monounsaturated fatty acids are only weak ligands and saturated fatty acids poor ligands. Moreover, downregulation 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, especially 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 triacylglycerol 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 factors. It is under the tight control of intracellular NEFA levels and composition, but also other metabolic and hormonal factors (e.g. carbohydrate, alcohol, insulin). Despite the complexity and degree of co-ordination of the liver lipid machinery, the overow of any metabolite pool and/or alteration of nuclear receptors sensing these can lead to organ function impairment and subsequent pathologies. References
Abo-Hashema, K. A.; Cake, M. H.; Power, G. W.; Clarke, D., 1999: Evidence for triacylglycerol synthesis in the lumen of microsomes via a lipolysis-esterication pathway involving carnitine acyltransferases. Journal of Biological Chemistry 274, 3557735582. Adeli, K.; Taghibiglou, C.; Van Iderstine, S. C.; Lewis, G. F., 2001: Mechanisms of hepatic very low-density lipoprotein overproduction in insulin resistance. Trends in Cardiovascular Medicine 11, 170176. Ahuja, H. S.; Szanto, A.; Nagy, L.; Davies, P. J., 2003: The retinoid X receptor and its ligands: versatile regulators of metabolic function, cell differentiation and cell death. Journal of Biological Regulators and Homeostatic Agents 17, 2945. Anderson, S. P.; Dunn, C.; Laughter, A.; Yoon, L.; Swanson, C.; Stulnig, T. M.; Steffensen, K. R.; Chandraratna, R. A.; Gustafsson, J. A.; Corton, J. C., 2004: Overlapping transcriptional programs regulated by the nuclear receptors peroxisome proliferator-activated receptor alpha, retinoid X receptor, and liver X receptor in mouse liver. Molecular Pharmacology 66, 14401452. Bandsma, R. H.; Wiegman, C. H.; Herling, A. W.; Burger, H. J.; ter, H. A.; Meijer, A. J.; Romijn, J. A.; Reijngoud, D. J.; Kuipers, F., 2001: Acute inhibition of glucose-6phosphate translocator activity leads to increased de

Table 1 Non-exhaustive list of liver genes involved in lipid metabolism, whose expression is regulated by fatty acids (after (Duplus and Forest, 2002; Pegorier et al., 2004) Please clarify liver genes/liver enzymes in the table caption 1) Downregulation ATP citrate-lyase Fatty acid synthase Spot 14 Stearoyl-CoA-desaturase Pyruvate kinase Upregulation Fatty acid translocase CD36 Fatty acid binding protein Acyl-CoA-sythetase Acyl-CoA-oxidase Carnitine palmitoyltransferase Cytochrome P450A2 Phosphoenolpyruvate carboxykinase Uncoupling proteins 2 and 3

Lipogenesis Lipogenesis Lipogenesis D9 desaturation Glycolysis Fatty acid transport across cell membrane Intracellular fatty acid binding Fatty acid activation Peroxisomal b-oxidation Transfer into mitochondria Microsomal x-oxidation Glyceroneogenesis Energy production

280

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

P. Nguyen et al.

Liver lipid metabolism

novo lipogenesis and development of hepatic steatosis without affecting VLDL production in rats. Diabetes 50, 25912597. Barish, G. D., 2006: Peroxisome proliferator-activated receptors and liver X receptors in atherosclerosis and immunity. Journal of Nutrition 136, 690694. Bergen, W. G.; Mersmann, H. J., 2005: Comparative aspects of lipid metabolism: impact on contemporary research and use of animal models. Journal of Nutrition 135, 24992502. Brindle, N. P.; Zammit, V. A.; Pogson, C. I., 1985: Regulation of carnitine palmitoyltransferase activity by malonyl-CoA in mitochondria from sheep liver, a tissue with a low capacity for fatty acid synthesis. Biochemical Journal 232, 177182. Clarke, S. D.; Jump, D. B., 1996: Polyunsaturated fatty acid regulation of hepatic gene transcription. Lipids 31(Suppl.), S711. Coleman, R. A.; Lee, D. P., 2004: Enzymes of triacylglycerol synthesis and their regulation. Progress in Lipid Research 43, 134176. Coleman, R. A.; Lewin, T. M.; Van Horn, C. G.; Gonzalez-Baro, M. R.; , 2002: Do long-chain acyl-CoA synthetases regulate fatty acid entry into synthetic versus degradative pathways? Journal of Nutrition 132, 21232126. Dentin, R.; Denechaud, P. D.; Benhamed, F.; Girard, J.; Postic, C., 2006: Hepatic gene regulation by glucose and polyunsaturated fatty acids: a role for ChREBP. Journal of Nutrition 136, 11451149. Dubuquoy, L.; Dharancy, S.; Nutten, S.; Pettersson, S.; Auwerx, J.; Desreumaux, P., 2002: Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet 360, 14101418. Duplus, E.; Forest, C., 2002: Is there a single mechanism for fatty acid regulation of gene transcription? Biochemical Pharmacology 64, 893901. Eberle, D.; Hegarty, B.; Bossard, P.; Ferre, P.; Foufelle, F., 2004: SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 86, 839848. Everett, L.; Galli, A.; Crabb, D., 2000: The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease. Liver 20, 191199. Gibbons, G. F.; Islam, K.; Pease, R. J., 2000: Mobilisation of triacylglycerol stores. Biochimica et Biophysica Acta 1483, 3757. Gondret, F.; Ferre, P.; Dugail, I., 2001: ADD-1/SREBP-1 is a major determinant of tissue differential lipogenic capacity in mammalian and avian species. Journal of Lipid Research 42, 106113. Grum, D. E.; Hansen, L. R.; Drackley, J. K., 1994: Peroxisomal beta-oxidation of fatty acids in bovine and rat liver. Comparative Biochemistry and Physiology. part B, Biochemistry and Molecular Biology 109, 281292.

Grummer, R. R., 1993: Etiology of lipid-related metabolic disorders in periparturient dairy cows. Journal of Dairy Science 76, 38823896. Hegardt, F. G. 1999: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. Biochemical Journal 338 (Pt 3), 569582. Hillgartner, F. B.; Salati, L. M.; Goodridge, A. G., 1995: Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis. Physiological Reviews 75, 4776. Hu, T.; Foxworthy, P.; Siesky, A.; Ficorilli, J. V.; Gao, H.; Li, S.; Christe, M.; Ryan, T.; Cao, G.; Eacho, P.; Michael, M. D.; Michael, L. F., 2005: Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha. Endocrinology 146, 53805387. Ide, T.; Shimano, H.; Yoshikawa, T.; Yahagi, N.; memiyaKudo, M.; Matsuzaka, T.; Nakakuki, M.; Yatoh, S.; Iizuka, Y.; Tomita, S.; Ohashi, K.; Takahashi, A.; Sone, H.; Gotoda, T.; Osuga, J.; Ishibashi, S.; Yamada, N., 2003: Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling.. Molecular Endocrinology 17, 12551267. Julius, U., 2003: Inuence of plasma free fatty acids on lipoprotein synthesis and diabetic dyslipidemia. Experimental and Clinical Endocrinology and Diabetes 111, 246 250. Jump, D. B.; Botolin, D.; Wang, Y.; Xu, J.; Christian, B.; Demeure, O., 2005: Fatty acid regulation of hepatic gene transcription. Journal of Nutrition 135, 25032506. Kendrick, J. S.; Wilkinson, J.; Cartwright, I. J.; Lawrence, S.; Higgins, J. A., 1998: Regulation of the assembly and secretion of very low density lipoproteins by the liver. Biological Chem 379, 10331040. Kerner, J.; Hoppel, C., 2000: Fatty acid import into mitochondria. Biochimica et Biophysica Acta 1486, 117. Kim, K. H., 1997: Regulation of mammalian acetyl-coenzyme A carboxylase. Annual Review of Nutrition 17, 77 99. Kim, H. J.; Miyazaki, M.; Man, W. C.; Ntambi, J. M., 2002: Sterol regulatory element-binding proteins (SREBPs) as regulators of lipid metabolism: polyunsaturated fatty acids oppose cholesterol-mediated induction of SREBP-1 maturation. Annals of NewYork Academy of Sciences 967, 3442. Kleppe, B. B.; Aiello, R. J.; Grummer, R. R.; Armentano, L. E.; , 1988: Triglyceride accumulation and very low density lipoprotein secretion by rat and goat hepatocytes in vitro. Journal of Dairy Science 71, 18131822. Latruffe, N.; Cherkaoui, M. M.; Nicolas-Frances, V.; Jannin, B.; Clemencet, M. C.; Hansmannel, F.; PassillyDegrace, P.; Berlot, J. P., 2001: Peroxisome-proliferator-activated receptors as physiological sensors of fatty

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

281

Liver lipid metabolism

P. Nguyen et al.

acid metabolism: molecular regulation in peroxisomes. Biochemical Society Transactions 29, 305309. Leveille, G. A.; Romsos, D. R.; Yeh, Y.; OHea, E. K., 1975: Lipid biosynthesis in the chick. A consideration of site of synthesis, inuence of diet and possible regulatory mechanisms. Poultry Science 54, 10751093. Liao, W.; Hui, T. Y.; Young, S. G.; Davis, R. A., 2003: Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER. Journal of Lipid Research 44, 978985. Mason, T. M., 1998: The role of factors that regulate the synthesis and secretion of very-low-density lipoprotein by hepatocytes. Critical Reviews in Clinical Laboratory Sciences 35, 461487. McGarry, J. D.; Woeltje, K. F.; Kuwajima, M.; Foster, D. W., 1989: Regulation of ketogenesis and the renaissance of carnitine palmitoyltransferase. Diabetes/Metabolism Reviews 5, 271284. OHea, E. K.; Leveille, G. A., 1969: Signicance of adipose tissue and liver as sites of fatty acid synthesis in the pig and the efciency of utilization of various substrates for lipogenesis. Journal of Nutrition 99, 338344. Patel, M. S.; Owen, O. E.; Goldman, L. I.; Hanson, R. W., 1975: Fatty acid synthesis by human adipose tissue. Metabolism 24, 161173. Pegorier, J. P.; Le, M. C.; Girard, J., 2004: Control of gene expression by fatty acids. Journal of Nutrition 134, 2444S2449S. Pullen, D. L.; Liesman, J. S.; Emery, R. S., 1990: A species comparison of liver slice synthesis and secretion of triacylglycerol from nonesteried fatty acids in media. Journal of Animal Science 68, 13951399. Reshef, L.; Olswang, Y.; Cassuto, H.; Blum, B.; Croniger, C. M.; Kalhan, S. C.; Tilghman, S. M.; Hanson, R. W., 2003: Glyceroneogenesis and the triglyceride/ fatty acid cycle. Journal of Biological Chemistry 278, 3041330416. Richard, M. J.; Holck, J. T.; Beitz, D. C., 1989: Lipogenesis in liver and adipose tissue of the domestic cat (Felis domestica). Comparative Biochemistry and Physiology B 93, 561564. Schonfeld, G.; Peger, B., 1971: Utilization of exogenous free fatty acids for the production of very low density lipoprotein triglyceride by livers of carbohydrate-fed rats. Journal of Lipid Research 12, 614621. Schoonjans, K.; Staels, B.; Auwerx, J., 1996: The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochimica et Biophysica Acta 1302, 93109. Simpson, A. E., 1997: The cytochrome P450 4 (CYP4) family. General Pharmacology 28, 351359. Smith, S.; Witkowski, A.; Joshi, A. K., 2003: Structural and functional organization of the animal fatty acid synthase. Progress in Lipid Research 42, 289317.

Stangassinger, M.; Kaspar, W.; Giesecke, D., 1986: The role of adipose and hepatic tissues in the lipogenesis of the dog. Comparative Biochemistry and Physiology B 85, 6769. Sul, H. S.; Latasa, M. J.; Moon, Y.; Kim, K. H., 2000: Regulation of the fatty acid synthase promoter by insulin. Journal of Nutrition 130, 315S320S. Taghibiglou, C.; Carpentier, A.; Van Iderstine, S. C.; Chen, B.; Rudy, D.; Aiton, A.; Lewis, G. F.; Adeli, K., 2000: Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. Journal of Biological Chemistry 275, 84168425. Travers, M. T.; Vernon, R. G.; Barber, M. C., 1997: Repression of the acetyl-CoA carboxylase gene in ovine adipose tissue during lactation: the role of insulin responsiveness. Journal of Molecular Endocrinology 19, 99107. Tsukamoto, H., 2005: Fat paradox in liver disease. Keio Journal of Medicine 54, 190192. Volpe, J. J.; Vagelos, P. R., 1974: Regulation of mammalian fatty-acid synthetase. The roles of carbohydrate and insulin. Proceedings of the National Academy of Sciences of the United States of America 71, 889893. White, D. A.; Bennett, A. J.; Billett, M. A.; Salter, A. M., 1998: The assembly of triacylglycerol-rich lipoproteins: an essential role for the microsomal triacylglycerol transfer protein. British Journal of Nutrition 80, 219 229. Wiegman, C. H.; Bandsma, R. H.; Ouwens, M.; van der Sluijs, F. H.; Havinga, R.; Boer, T., Reijngoud, D. J.; Romijn, J. A.; Kuipers, F., 2003: Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin. Diabetes 52, 10811089. Willy, P. J.; Mangelsdorf, D. J., 1997: Unique requirements for retinoid-dependent transcriptional activation by the orphan receptor LXR. Genes and Development 11, 289298. Xu, J.; Nakamura, M. T.; Cho, H. P.; Clarke, S. D., 1999: Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. Journal of Biological Chemistry 274, 2357723583. Yamamoto, T.; Shimano, H.; Inoue, N.; Nakagawa, Y.; Matsuzaka, T.; Takahashi, A.; Yahagi, N.; Sone, H.; Suzuki, H.; Toyoshima, H.; Yamada, N., 2007: Protein Kinase A suppresses SREBP-1c expression via phosphorylation of LXR in the liver. Journal of Biological Chemistry 282, 1168711695.

282

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

P. Nguyen et al.

Liver lipid metabolism

Yokoyama, S., 2006: Assembly of high-density lipoprotein. Arteriosclerosis, Thrombosis, and Vascular Biology 26, 2027. Yoshikawa, T.; Ide, T.; Shimano, H.; Yahagi, N.; memiyaKudo, M.; Matsuzaka, T.; Yatoh, S.; Kitamine, T.; Okazaki, H.; Tamura, Y.; Sekiya, M.; Takahashi, A.; Hasty, A. H.; Sato, R.; Sone, H.; Osuga, J.; Ishibashi, S.; Yamada, N., 2003: Cross-talk between peroxisome

proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling.. Molecular Endocrinology 17, 12401254. Zelcer, N.; Tontonoz, P., 2006: Liver X receptors as integrators of metabolic and inammatory signaling. Journal of Clinical Investigation 116, 607614.

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

283