Journal of LipidsVolume 2012 (2012), Article ID 139875, 10 pagesdoi:10.1155/2012/139875

Review Article

Nuclear Receptors in Nonalcoholic Fatty Liver Disease

Jorge A. López-Velázquez, Luis D. Carrillo-Córdova, Norberto C. Chávez-Tapia, Misael Uribe, and Nahum Méndez-Sánchez

Liver Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Colonia Toriello Guerra, 14050 Tlalpan, Mexico City, Mexico

Received 16 August 2011; Accepted 14 September 2011

Academic Editor: Piero Portincasa

Copyright © 2012 Jorge A. López-Velázquez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Nuclear receptors comprise a superfamily of ligand-activated transcription factors that are involved in important aspects of hepatic physiology and pathophysiology. There are about 48 nuclear receptors in the human. These nuclear receptors are regulators of many hepatic processes including hepatic lipid and glucose metabolism, bile acid homeostasis, drug detoxification, inflammation, regeneration, fibrosis, and tumor formation. Some of these receptors are sensitive to the levels of molecules that control lipid metabolism including fatty acids, oxysterols, and lipophilic molecules. These receptors direct such molecules to the transcriptional networks and may play roles in the pathogenesis and treatment of nonalcoholic fatty liver disease. Understanding the mechanisms underlying the involvement of nuclear receptors in the pathogenesis of nonalcoholic fatty liver disease may offer targets for the development of new treatments for this liver disease.

1. Introduction

Liver diseases are a serious problem throughout the world. In Mexico, since 2000, cirrhosis and other chronic liver diseases have become among the main causes of mortality [1]. The incidence and prevalence of liver diseases are increasing along with changes in lifestyle and population aging, and these diseases were responsible for 20,941 deaths in 2007 [2].

In Mexico, the incidence of metabolic syndrome is also increasing. The metabolic syndrome has recently been associated with nonalcoholic fatty liver disease (NAFLD), and about 90% of patients with NAFLD have more than one feature of the metabolic syndrome [3]. The severity of NAFLD is one factor contributing to the development of nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma [4, 5]. The growing obesity epidemic requires a better understanding of the genetic networks and signal transduction pathways that regulate the pathogenesis of these conditions. A clear definition of the mechanisms responsible for metabolic control may provide new knowledge for the development of new drugs, with novel mechanisms of action, for the treatment of chronic liver diseases.

The ability of individual nuclear receptors (NRs) to regulate multiple genetic networks in different tissues and their own ligands may represent a new class of potential drugs targets. To elucidate the challenges involved in developing such drugs, this paper focuses on the role of hepatic NRs in lipid metabolism and the possible effects on the physiopathology of NAFLD.

2. Nonalcoholic Fatty Liver Disease

NAFLD is defined by the accumulation of triglycerides in the form of droplets (micro- and macrovesicles) within hepatocytes [6]. The mechanism involves impaired insulin regulation, which affects fat and glucose metabolism (intermediary metabolism) in the liver, skeletal muscle, and adipose tissue, a condition known as insulin resistance. Insulin resistance increases free fatty acids and hepatic de novo lipogenesis, causes dysfunction in fatty acid oxidation, and alters very-low-density lipoprotein (VLDL) triglyceride export [7].

NAFLD is associated with insulin resistance, obesity, and a lifestyle characterized by physical inactivity and an unlimited supply of high-fat foods. However, more recent studies have proposed that not all individuals with NAFLD develop insulin resistance before the presence of a fatty liver [3, 8].

NAFLD is a cluster of metabolic, histological, and molecular disorders characterized by liver injury [9]. The purpose of this paper is to describe the complex working of NRs and their role in the hepatic accumulation of fat independent of excessive alcohol consumption.

NRs are ligand-activated transcription factors that have a broad range of metabolic, detoxifying, and regulatory functions. NRs are sensitive to the levels of many natural and synthetic ligands including hormones, biomolecules (lipids), vitamins, bile acids, metabolites, drugs, and xenobiotic toxins. In addition to their functions at the hepatic level, NRs also control hepatic inflammation, regeneration, fibrosis, and tumor formation [10]. These functions can be understood through a complex transcriptional network that allows them to maintain cellular nutrient homeostasis, to protect against toxins by limiting their uptake and facilitating their metabolism and excretion, and to play a role in several key steps in inflammation and fibrosis [11].

New knowledge about the functions of NRs helps clarify the pathogenesis and pathophysiology of a wide spectrum of hepatic disorders (see Table 1).

Table 1: Nuclear receptors in hepatic lipid metabolism.

RXR partner
Ligands
Official name
Role in hepatic lipid metabolism

LXR
Oxysterols (22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, 24(S),25-epoxycholesterol, 27-hydroxycholesterol) and fatty acids
NR1H3
(i) Increases fatty acid synthesis, TG level, HDL level, cholesterol secretion

(ii) Upregulation of SREBP-c

(iii) Upregulation of ChREBP, Angptl3

(iv) Downregulation of ApoA-V

PPAR
Fatty acids, fibrates, statins, eicosanoids, and leukotrienes
NR1C1
(i) Promotes fatty acid oxidation (by lipoprotein lipase activation)

(ii) Improves insulin resistance

(iii) Suppression: acyl CoA oxidase (ACO-OX), acyl CoA synthase (ACS), enoyl-CoA hydratase, malic enzyme, HMG-CoA synthase, mitochondrial enzymes, APOA1 and APOCIII

FXR
Bile acids, pregnadiene, and fexaramine
NR1H4
(i) Induces lipoprotein metabolism genes/clearance represses hepatic genes involved in the synthesis of TG

(ii) Induces human PPAR

(iii) Increases hepatic expression of receptors VLDL

(iv) Reduces: hepatic lipogenesis and plasma triglyceride and cholesterol levels

(v) Decreases expression of proteins apoC-III and Angptl3 (inhibitors of LPL)

PXR
Pregnanes, progesterone, and glucocorticoids, LCA, xenobiotics/drugs, rifampicin
NR1I2
(i) Induces lipogenesis by increasing expression of the fatty acid translocase CD36, SCD-1, and long-chain free fatty acid elongase

(ii) Suppression of several genes involved in fatty acid -oxidation (PPAR, thiolase, carnitine palmitoyltransferase 1a (Cpt1a), and mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 (Hmgcs2))

CAR
Androstane metabolites, estrogens, progesterone, and xenobiotics
NR1I3
(i) Induction of Insig-1, a protein with antilipogenic

properties

(ii) Interacts with PPAR during fasting

(iii) Suppresses lipid metabolism and lowers serum triglyceride level by reducing SREBP-1 level

3. Nuclear Receptor Structure

The NRs are characterized by a central DNA-binding domain, which targets the receptor to specific DNA sequences known as hormone-response elements. The DNA-binding domain comprises two highly conserved zinc fingers that isolate the nuclear receptors from other DNA-binding proteins. The C-terminal half of the receptor encompasses the ligand-binding domain, which possesses the essential property of ligand recognition and ensures both specificity and selectivity of the physiological response [12, 13]. The predominant role of these receptors is the transcriptional regulation of enzymes and other proteins involved in energy homeostasis (Figure 1(a)).

(a)

(b)

Figure 1: (a) Schematic representation of a typical nuclear receptor. Nuclear receptors may be divided into five regions based on structural and functional similarities (denoted A, B, C, D, E, and F). Regions C and E contain the conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) that are the signature of this superfamily. In addition, the constitutive transport element (CTE) is a dimerization region within the LBD and two transactivation domains (denoted AF-1 and AF-2/τc). A second dimerization domain (not shown) exists in the DBD and is required for heterodimerization of receptors on response elements. (b) NR function. Ligand binding to NRs triggers changes in their conformation leading to the dissociation of corepressors and the recruitment of coactivators. After this exchange of coregulators, RNA polymerase II is recruited and mRNA transcription is initiated. Most NRs bind to their DNA response elements in a sequence-specific manner as dimers, functioning either as homodimers or as heterodimers with the RXR. RA: retinoic acid. Modified from [13, 94].

4. Action Mode of Nuclear Receptors

NRs act in three steps [14]: repression, derepression, and transcription activation. Repression is characteristic of the apo-NR, which recruits a corepressor complex with histone deacetylase activity. Derepression occurs following ligand binding, which dissociates this complex and recruits the first coactivator complex, with histone acetyltransferase activity, and causes chromatin decondensation, which is believed to be necessary, but not sufficient, for activation of the target gene. In the third step, transcription activation, the histone acetyltransferase complex dissociates to cause the assembly of a second coactivator, which can establish contact with the basal transcriptional machinery to activate the target gene [15] (Figure 1(b)).

Coactivators are molecules recruited by ligand-bound activated NRs (or other DNA-binding transcription factors) that increase gene expression. Coactivators contribute to the transcriptional process through a diverse array of enzymatic activities such as acetylation, methylation, ubiquitination, and phosphorylation, or as chromatin remodelers [16].

The result is the modulation of the expression of a wide array of physiologically important groups of genes involved in diverse pathological processes including cancer, inherited genetic diseases, metabolic disorders, and inflammation.

In contrast to the coactivator function, corepressors interact with NRs that are not bound to the ligand and repress transcription. Corepressor-associated proteins such as histone deacetylases enforce a local chromatin environment that opposes the transcription-promoting activities of coactivators [17].

5. Nuclear Receptors in the Liver

The hepatocyte is responsible for processes involved in providing for many of the body’s metabolic needs, including the synthesis and control of the pathways involved in the metabolism of cholesterol, fatty acids, carbohydrates, amino acids, serum proteins, and bile acids, and the detoxification of drugs and xenobiotics.

The hepatocyte employs multiple levels of regulation to perform its functions and possesses self-protective processes to avoid self-destruction. Some members of the NR superfamily provide hepatic mechanisms for self-regulation in hepatocytes [18].

Gene regulation by NRs is more complex than simply the presence of a potential DNA recognition sequence in a promoter. Rather, it is a complex and multilayered process that involves competition between agonists and antagonists, heterodimerization, coregulator recruitment, and NR protein modification.

The NR family comprises 48 family members and is the largest group of transcriptional regulators in the human. Because some NRs participate in the control of hepatic homeostasis, they may provide a new therapeutic target for the treatment of liver diseases such as NAFLD [19].

5.1. Liver X Receptor

The transcriptional factor liver X receptor (LXR) is involved in cholesterol metabolism. The LXR gene encodes two distinct products, LXRα and LXRβ, each with diverse patterns of expression but similar target DNA-binding elements and ligands. The human LXRα gene is located on chromosome 11p11.2, and the human LXRβ gene is located on chromosome 19q13.3. We will focus on LXRα because of its high expression in the liver, although it is also expressed at lower levels in the kidney, intestine, lung, fat, adrenal, spleen, and macrophages [20, 21]. The ligands for LXR are oxysterols. Once activated, LXR induces the expression of a cluster of genes that function in lipid metabolism; these functions are cholesterol absorption, efflux, transport, and excretion [22–24]. Besides its metabolic role, LXRs also modulate immune and inflammatory responses in macrophages [25].

Like most other nuclear receptors, LXR forms heterodimers with the retinoid X receptor (RXR) within the nucleus. Binding of the RXR to LXR leads to the formation of a complex with corepressors such as silencing mediator of retinoic acid, thyroid hormone receptor, and nuclear corepressor [26].

In the absence of a ligand, these corepressor interactions are maintained and the transcriptional activity of target genes is suppressed. Binding of a ligand to LXR causes a conformational change that facilitates inactivation of the corepressor complex and the transcription of target genes [27].

LXR is a key regulator of whole-body lipid and bile acid metabolism [20, 28] (Figure 2). LXR regulates a cluster of genes that participate in the transport of excess cholesterol in the form of high-density lipoprotein (HDL) from peripheral tissue to the liver—a process called reverse cholesterol transport. In vivo activation of LXR with a synthetic, high-affinity ligand increases the HDL level and net cholesterol secretion [29]. LXR positively regulates several enzymes involved in lipoprotein metabolism including lipoprotein lipase (LPL), human cholesteryl ester transport protein, and the phospholipid transfer protein [30]. LXR also regulates the crucial bile acid enzyme CYP7A1. In rodents, this enzyme contains an LXR response element that is upregulated in response to excess cholesterol in the diet. The enzymatic activation and conversion of cholesterol to bile acids is one mechanism for handling excess dietary cholesterol [31–33].

Figure 2: NRs as central regulators of hepatic lipid metabolism. Oxysterols activate the LXR, whereas bile acids (BA) stimulate SHP expression through the FXR (not shown). The LXR activates SREBP-1c and induces de novo fatty acid (FA) synthesis and hypertriglyceridemia by activating FAS, ACC, SCD1, and ChREBP (a glucose-sensitive transcription factor that promotes the hepatic conversion of carbohydrates into lipids). Several important proteins that could mediate the LXR-mediated hypertriglyceridemic effect are regulated. One protein is angiopoietin-like protein 3 (Angptl3), a liver-secreted protein that increases both plasma triglyceride level by inhibiting LPL activity in different tissues and free fatty acid level by activating lipolysis in adipocytes. LXR activation increases the expression of Angptl3 and LPL and downregulates apoA-V expression. Activation of the FXR leads to the repression of hepatic lipogenesis by reducing the expression of SREBP-1c. By increasing the expression of PPARα, the FXR also promotes FFA catabolism via β-oxidation, which induces ACO-OX, ACS, ECA, HMG-CoAS, FAB1, and FATP. By repressing the expression of MTP, an enzyme that controls VLDL assembly, the FXR reduces VLDL production. Activation of the FXR increases TG clearance by promoting LPL activity, via induction of ApoC-II and B1R. Activation of the FXR also reduces TG clearance by decreasing the expression of ApoC-III and Angptl3, two LPL inhibitors. PPARα can be activated by FXR and fibrates (not shown). PPAR activation leads to β-oxidation, which induces ACO-Ox, ACS, ECA, HMG-CoAS, FAB1, and FATP. Others genes are regulated. For example, LPL, which is involved in the degradation of TG, is activated, and APOA1 and APOCIII are both downregulated. The activation pathways are shown by green arrows, inhibitory pathways by red lines, and inhibited activation pathways by broken green arrows. Angptl3: angiopoietin-like protein 3; ACC: acetyl-CoA carboxylase; Apo: apolipoprotein; ChREBP: carbohydrate response element-binding protein; FAS: fatty acid synthase; FATP: fatty acid transport protein; FXR: farnesoid X receptor; LPL: lipoprotein lipase; LXR: liver X receptor; MTP: microsomal triglyceride transfer protein; PPAR: peroxisome proliferator-activated receptor; SCD1: stearoyl-coenzyme A desaturase 1; SREBP-1c: sterol regulatory element-binding protein-1c; TG: triglyceride. Arrows and stop bars indicate positive regulation or activation and negative regulation or repression, respectively.

In addition to its ability to modulate cholesterol and bile acid metabolism, LXR is also a key regulator of hepatic lipogenesis. Its lipogenic activity results from the upregulation of the master regulator of hepatic lipogenesis sterol regulatory element-binding protein-c (SREBP-c) and from the induction of fatty acid synthase, acyl coenzyme A carboxylase, and stearoyl CoA desaturase 1, all leading to increased hepatic lipid levels [34, 35], one of the etiological agents in the pathogenesis of NAFLD. Moreover, LXR induces the carbohydrate-response element-binding protein, ChREBP [36]. ChREBP is a target gene of LXR and is a glucose-sensitive transcription factor that promotes the hepatic conversion of carbohydrates into lipids. Several important proteins might mediate the LXR-mediated hypertriglyceridemic effect. These include angiopoietin-like protein 3 (Angptl3) [37], a liver-secreted protein that increases the concentrations of both plasma triglycerides by inhibiting LPL activity in different tissues and free fatty acids by activating lipolysis in adipocytes and/or apoA-V. LXR activation increases Angptl3 expression and downregulates apoA-V expression [38]. The second “hit” in NAFLD is related to the proinflammatory molecules, whose expression is repressed by LXR. These include inducible nitric oxide synthase, cyclooxygenase 2, interleukin-6 (IL-6), IL-1β, chemokine monocyte chemoattractant protein-1, and chemokine monocyte chemoattractant protein-3 [39].

LXR-activated pathways play central roles in whole-body lipid metabolism by regulating multiple pathways in liver cells. Further investigation into the effects of synthetic LXR-specific agonists and/or antagonists may provide new therapeutic tools for the treatment of NAFLD.

5.2. Peroxisome Proliferator-Activated Receptors

NAFLD appears to be a link between insulin resistance and obesity. Several recent studies have shown that a family of transcription factors, named the peroxisome-proliferator-activated receptors (PPARs), improve several of the metabolic abnormalities associated with insulin resistance and impaired fat metabolism [40].

The PPARs are nuclear hormone receptors. Three isotypes have been identified in humans: PPARα, PPARβ/δ, and PPARγ [41]. These receptors exhibit different tissue distribution and functions and, to some extent, different ligand specificities. PPARα is highly expressed in the liver, brown adipose tissue, heart, skeletal muscle, kidney, and at lower levels in other organs. PPARγ is highly expressed in adipose tissues and is present in the colon and lymphoid organs. PPARβ/δ is expressed ubiquitously, but its levels may vary considerably [42, 43].

Mechanistically, the PPARs also form heterodimers with the RXR and activate transcription by binding to a specific DNA element, termed the peroxisome proliferator response element (PPRE), in the regulatory region of several genes encoding proteins that are involved in lipid metabolism and energy balance. Binding of agonists causes a conformational change that promotes the binding to transcriptional coactivators. Conversely, binding of antagonists induces a conformation that favors the binding of corepressors. Physiologically, PPAR-RXR heterodimers may bind to PPREs in the absence of a ligand, although the transcriptional activation depends on the ligand-bound PPAR-RXR [44, 45]. The predominant role of these receptors is the transcriptional regulation of enzymes and other proteins involved in energy homeostasis, some of which are in the liver. To explain their possible action in the development and treatment of NAFLD, a brief description of each PPAR follows [46, 47].

In the liver, PPARα promotes fatty acid oxidation. It is the target for the hypolipidemic fibrates, such as fenofibrate, clofibrate, and gemfibrozil, which are used in the treatment of hypertriglyceridemia [48].

The role of PPARα in hepatic fatty acid metabolism is especially prominent during fasting. In fasted PPAR-null mice, its absence is associated with pronounced hepatic steatosis, decreased levels of plasma glucose and ketone bodies, and elevated plasma free fatty acids levels, and hypothermia. These severe metabolic disturbances are the result of the decreased expression of many genes involved in hepatic lipid metabolism. The PPARα target genes are those for acyl CoA oxidase (ACO-OX), acyl CoA synthase (ACS), enoyl-CoA hydratase, malic enzyme, HMG CoA synthase, mitochondrial enzymes, liver-fatty-acid-binding protein, and fatty acid transport protein. PPARα can also regulate other genes such as LPL, which is involved in the degradation of triglycerides, and APOA1 and APOCIII, which are both downregulated by PPARα [49–55] (Figure 2).

Whereas PPARα controls lipid catabolism and homeostasis in the liver, PPARγ promotes the storage of lipids in adipose tissues and plays a pivotal role in adipocyte differentiation. It is a target of the insulin-sensitizing thiazolidinediones. Despite its relatively low expression levels in healthy liver, PPARγ is critical for the development of NAFLD [56].

In the liver, PPARβ/δ is protective against liver toxicity induced by environmental chemicals, possibly by downregulating the expression of proinflammatory genes. PPARβ/δ regulates glucose utilization and lipoprotein metabolism by promoting reverse cholesterol transport [57–60]. PPARs appear to be targets for the treatment of metabolic disorders. PPARα and PPARγ are already therapeutic targets for the treatment of hypertriglyceridemia and insulin resistance, respectively, disorders that relate directly to the progress of NAFLD. The discovery of more pathways may provide new treatments for hepatopathies.

5.3. Farnesoid X Receptor

The farnesoid X receptor (FXR), a member of the NR superfamily, has a typical NR structure and contains a hydrophobic pocket that accommodates lipophilic molecules such as bile acids [61]. Its gene is located on chromosome 12, and it is expressed predominantly in the liver, gut, kidneys, and adrenals and at lower levels in white adipose tissue [62, 63]. The FXR binds to specific response elements as a heterodimer with the RXR, although it has also been reported to bind DNA as a monomer [28, 64]. The main physiological role of the FXR is to act as a bile acid sensor in the enterohepatic tissues. FXR activation regulates the expression of various transport proteins and biosynthetic enzymes crucial to the physiological maintenance of bile acids and lipid and carbohydrate metabolism.

Bile acids bind to and activate this NR. The order of potency of FXR binding to bile acids is chenodeoxycholic acid > lithocholic acid = deoxycholic acid > cholic acid [65, 66].

In addition to their well-established roles in bile acid metabolism, recent data have demonstrated that activation of the FXR is also implicated in lipid metabolism. Activation of the FXR reduces both hepatic lipogenesis and plasma triglyceride and cholesterol levels, induces the genes implicated in lipoprotein metabolism/clearance, and represses hepatic genes involved in the synthesis of triglycerides [67]. The FXR promotes reverse transport of cholesterol by increasing hepatic uptake of HDL cholesterol via two independent mechanisms. The first is FXR-mediated suppression of hepatic lipase expression [68]. Hepatic lipase reduces HDL particle size by hydrolyzing its triglycerides and phospholipids in hepatic sinusoids, which facilitates hepatic uptake of HDL cholesterol. The second mechanism is the induction by the FXR of the expression of the gene for scavenger receptor B1, the HDL uptake transporter in the liver [69].

Activation of the FXR also increases the hepatic expression of receptors such as VLDL receptor and syndecan-1, which are involved in lipoprotein clearance, and increases the expression of ApoC-II, which coactivates lipoprotein lipase (LPL). FXR activation also decreases the expression of proteins such as ApoC-III and Angptl3 [70] that normally function as inhibitors of LPL. Finally, the FXR induces human PPARα [71], an NR that functions to promote fatty acid β-oxidation. Taken together, these data suggest that FXR activation lowers plasma triglyceride levels via both repressing SREBP1-c and triglyceride secretion and increasing the clearance of triglyceride-rich lipoproteins from the blood (Figure 2).

In carbohydrate metabolism, activation of the hepatic FXR regulates gluconeogenesis, glycogen synthesis, and insulin sensitivity [72]. The bile acid sensor FXR also has anti-inflammatory properties in the liver and intestine, mainly by interacting with NF-κB signaling. FXR agonists might therefore represent useful agents to reduce inflammation in cells with high FXR expression levels, such as hepatocytes, and to prevent or delay cirrhosis and cancer development in inflammation-driven liver diseases.

These data suggest that FXR activation by its ligands would reduce hepatic steatosis and that such activation may have a beneficial role in NAFLD by decreasing hepatic de novo lipogenesis, which constitutes the first “hit” of the disease. Inflammatory processes lead to the development of hepatitis and subsequent liver fibrosis. The hepatic FXR appears to be downregulated during the acute-phase response in rodents in a manner similar to that seen for other NRs such as PPARα and the LXR [73].

5.4. The Pregnant X Receptor and Constitutive Androstane Receptor

The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) share some common ligands and have an overlapping target gene pattern. The CAR gene is the product of the NR1I3 gene located on chromosome 1, locus 1q23, whereas hPXR is the product of the NR1I2 gene, which is located on chromosome 3, locus 3q12–q13.3 [74–76]. Like most other NRs, the PXR and CAR have an N-terminal DNA-binding domain and a C-terminal ligand-binding domain. PXR and CAR regulate gene expression by forming heterodimers with the RXR.

The PXR is located in the nucleus and has a low basal activity and is highly activated upon ligand binding [77, 78]. By contrast, in the noninduced state, the CAR resides in the cytoplasm. Compounds that activate the CAR and PXR are structurally very diverse; most are small and are highly lipophilic [79]. The PXR is activated by pregnanes, progesterone, and glucocorticoids [80, 81], whereas the CAR is affected both positively and negatively by androstane metabolites, estrogens, and progesterone [82, 83]. For this reason, in addition to functioning as xenobiotic receptors, the PXR and CAR are thought to be endobiotic receptors that influence physiology and diseases [84, 85].

For example, several studies have shown that the PXR induces lipogenesis in a SREBP-independent manner. Lipid accumulation and marked hepatic steatosis in PXR-transgenic mice are associated with increased expression of the fatty acid translocase CD36 (also called FAT) and several accessory lipogenic enzymes, such as SCD-1 and long-chain free fatty acid elongase. CD36, a multiligand scavenger receptor present on the surface of a number of cell types, may contribute to hepatic steatosis by facilitating the high-affinity uptake of fatty acids from the circulation [86]. The CD36 level in the liver correlates with hepatic triglyceride storage and secretion, suggesting that CD36 plays a causative role in the pathogenesis of hepatic steatosis [87]. PXR may also promote hepatic steatosis by increasing the expression of CD36 directly or indirectly through the PXR-mediated activation of PPARγ [86].

Interestingly, an independent study showed that hepatic triglyceride level decreases temporarily after short-term (10-hour) activation of the PXR [88]. PXR activation is also associated with upregulation of PPARγ, a positive regulator of CD36 and a master regulator of adipogenesis [89]. PXR activation is also associated with suppression of several genes involved in fatty acid β-oxidation, such as PPARα and thiolase [90]. A study by Nakamura and colleagues showed that PXR represses β-oxidation-related genes such as carnitine palmitoyltransferase 1a (Cpt1a) and mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 (Hmgcs2) through crosstalk with the insulin-responsive forkhead box factor A2 (FoxA2) (Figure 3).

Figure 3: Activation of the PXR induces lipogenesis and inhibits fatty acid β-oxidation. The PXR induces lipogenesis through activation of CD36, PPARγ, SCD1, and FAE gene expression. The PXR inhibits fatty acid β-oxidation through its suppression of PPARα and thiolase gene expression. In addition, PXR binds to FoxA2, a key regulator of β-oxidation, and inhibits FoxA1-mediated activation of Cpt1a and Hmgcs2 gene expression. CAR activation inhibits lipogenesis by inducing Insig-1, a protein that plays a role in SREBP-mediated regulation of lipogenic genes. Insig proteins bind and trap SCAP, retaining it in the ER and preventing it from escorting SREBPs to the site of proteolytic activation in the Golgi complex (not shown). SREBPs are cleaved by two proteases in the Golgi complex, and the bHLH-Zip domain of SREBPs transfers from the membrane to the nucleus to bind the sterol response elements in the promoter region of the target genes (not shown). CAR inhibits fatty acid β-oxidation. CAR competes with PPARα for its binding site in the 3-hydroxyacyl CoA dehydrogenase gene promoter. Activation of CAR also decreases the expression of Cpt1, a rate-limiting enzyme of β-oxidation. Arrows and stop bars indicate positive regulation or activation and negative regulation or repression, respectively. Cpt1a: carnitine palmitoyltransferase 1a; FAE: long-chain free fatty acid elongase; FoxA2: forkhead box factor A2; Hmgcs2: mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2; PPAR: peroxisome proliferator-activated receptor; SCAP: SREBP cleavage-activating protein; SCD1: stearoyl CoA desaturase 1; SREBP: sterol regulatory-element binding protein.

Activation of the CAR might suppress lipid metabolism and lower serum triglyceride levels by reducing the level of SREBP-1, a master regulator of lipid metabolism. The inhibitory effects of the CAR on lipid metabolism might also be attributed to induction of Insig-1, a protein with antilipogenic properties [88].

The CAR interacts with PPARα during fasting and has been reported to interfere with fatty acid metabolism by binding to DNA elements overlapping with the PPARα-binding site in the promoter region of 3-hydroxyacyl CoA dehydrogenase, an important enzyme in peroxisomal fatty acid β-oxidation [91] (Figure 3).

Finally, other studies indicate that the CAR might be involved in the pathogenesis of NASH [92] by regulating the response of serum triglyceride level to metabolic stress [93]. The overlap of the activation of endogenous lipids by the CAR and PXR suggests a functional connection between these receptors in liver physiology. This knowledge might be useful in the development of new treatments to limit or prevent the pathogenesis of NAFLD by developing agonists or antagonists to prevent or lessen lipid accumulation within the liver parenchyma.

6. Conclusion

NAFLD encompasses a spectrum of conditions characterized histologically by hepatic steatosis ranging from simple fatty liver to NASH cirrhosis and HCC [4].

NRs control fatty acid transport from peripheral adipose tissue to the liver and regulate several critical metabolic steps involved in the pathogenesis of NAFLD, including fat storage, export, uptake, oxidation, and lipolysis [94]. The discovery that many ligands activate the whole family of NRs (FXR, LXR, PPARs, PXR, and CAR) and their possible interconnected mechanisms that control lipid metabolism suggests the possibility of developing novel therapies for the treatment of NAFLD. The LXR and PXR regulate several metabolically relevant pathways and clusters of genes that lead to hepatic lipogenesis and might be directly related to the pathogenesis of liver diseases. The FXR, PPARα, and CAR are activated by ligands to orchestrate a broad range of lipolytic activities. These might become future candidates for drugs designed to target metabolic liver disorders.

Acknowledgments

This study was supported by grant from the Mexican National Research Council (CONACYT 62460) and from Medica Sur Clinic & Foundation.

References

N. Méndez-Sánchez, E. García-Villegas, B. Merino-Zeferino et al., “Liver diseases in Mexico and their associated mortality trends from 2000 to 2007: a retrospective study of the nation and the federal states,” Annals of Hepatology, vol. 9, no. 4, pp. 428–438, 2010.

N. Méndez-Sánchez, A. R. Villa, N. C. Chávez-Tapia et al., “Trends in liver disease prevalence in Mexico from 2005 to 2050 through mortality data,” Annals of Hepatology, vol. 4, no. 1, pp. 52–55, 2005.

N. Méndez-Sánchez, N. C. Chávez-Tapia, and M. Uribe, “Obesity and non-alcoholic steatohepatitis,” Gaceta Medica de Mexico, vol. 140, supplement 2, pp. S67–S72, 2004.

G. C. Farrell and C. Z. Larter, “Nonalcoholic fatty liver disease: from steatosis to cirrhosis,” Hepatology, vol. 43, no. 2, pp. S99–S112, 2006.

N. C. Chavez-Tapia, N. Méndez-Sánchez, and M. Uribe, “Role of nonalcoholic fatty liver disease in hepatocellular carcinoma,” Annals of Hepatology, vol. 8, supplement 1, pp. S34–S39, 2009.

N. Méndez-Sánchez, M. Arrese, D. Zamora-Valdés, and M. Uribe, “Current concepts in the pathogenesis of nonalcoholic fatty liver disease,” Liver International, vol. 27, no. 4, pp. 423–433, 2007.

M. Adiels, M. R. Taskinen, C. Packard et al., “Overproduction of large VLDL particles is driven by increased liver fat content in man,” Diabetologia, vol. 49, no. 4, pp. 755–765, 2006.

N. Méndez-Sánchez, N. C. Chavez-Tapia, D. Zamora-Valdés, and M. Uribe, “Adiponectin, structure, function and pathophysiological implications in non-alcoholic fatty liver disease,” Mini-Reviews in Medicinal Chemistry, vol. 6, no. 6, pp. 651–656, 2006.

C. A. Matteoni, Z. M. Younossi, T. Gramlich, N. Boparai, Y. C. Liu, and A. J. McCullough, “Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity,” Gastroenterology, vol. 116, no. 6, pp. 1413–1419, 1999.

M. Robinson-Rechavi, H. E. Garcia, and V. Laudet, “The nuclear receptor superfamily,” Journal of Cell Science, vol. 116, no. 4, pp. 585–586, 2003.

C. H. Lee and L. N. Wei, “Characterization of an inverted repeat with a zero spacer (IRO)-type retinoic acid response element from the mouse nuclear orphan receptor TR2-11 gene,” Biochemistry, vol. 38, no. 27, pp. 8820–8825, 1999.

D. J. Mangelsdorf, C. Thummel, M. Beato et al., “The nuclear receptor super-family: the second decade,” Cell, vol. 83, no. 6, pp. 835–839, 1995.

D. J. Mangelsdorf and R. M. Evans, “The RXR heterodimers and orphan receptors,” Cell, vol. 83, no. 6, pp. 841–850, 1995.

D. M. Lonard and B. W. O'Malley, “The expanding cosmos of nuclear receptor coactivators,” Cell, vol. 125, no. 3, pp. 411–414, 2006.

M. Beato, “Transcriptional control by nuclear receptors,” FASEB Journal, vol. 5, no. 7, pp. 2044–2051, 1991.

H. Gronemeyer, J. A. Gustafsson, and V. Laudet, “Principles for modulation of the nuclear receptor superfamily,” Nature Reviews Drug Discovery, vol. 3, no. 11, pp. 950–964, 2004.

D. M. Lonard, R. B. Lanz, and B. W. O'Malley, “Nuclear receptor coregulators and human disease,” Endocrine Reviews, vol. 28, no. 5, pp. 575–587, 2007.

S. J. Karpen, “Nuclear receptor regulation of hepatic function,” Journal of Hepatology, vol. 36, no. 6, pp. 832–850, 2002.

M. Arrese and S. J. Karpen, “Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseases,” Clinical Pharmacology and Therapeutics, vol. 87, no. 4, pp. 473–478, 2010.

T. T. Lu, J. J. Repa, and D. J. Mangelsdorf, “Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism,” Journal of Biological Chemistry, vol. 276, no. 41, pp. 37735–37738, 2001.

P. J. Willy, K. Umesono, E. S. Ong, R. M. Evans, R. A. Heyman, and D. J. Mangelsdorf, “LXR, a nuclear receptor that defines a distinct retinoid response pathway,” Genes and Development, vol. 9, no. 9, pp. 1033–1045, 1995.

S. B. Joseph, B. A. Laffitte, P. H. Patel et al., “Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors,” Journal of Biological Chemistry, vol. 277, no. 13, pp. 11019–11025, 2002.

J. D. Horton, J. L. Goldstein, and M. S. Brown, “SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver,” Journal of Clinical Investigation, vol. 109, no. 9, pp. 1125–1131, 2002.

J. J. Repa, G. Liang, J. Ou et al., “Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ,” Genes and Development, vol. 14, no. 22, pp. 2819–2830, 2000.

A. Castrillo and P. Tontonoz, “Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation,” Annual Review of Cell and Developmental Biology, vol. 20, pp. 455–480, 2004.

J. D. Chen and R. M. Evans, “A transcriptional co-repressor that interacts with nuclear hormone receptors,” Nature, vol. 377, no. 6548, pp. 454–457, 1995.

C. K. Glass and M. G. Rosenfeld, “The coregulator exchange in transcriptional functions of nuclear receptors,” Genes and Development, vol. 14, no. 2, pp. 121–141, 2000.

P. A. Edwards, H. R. Kast, and A. M. Anisfeld, “BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis,” Journal of Lipid Research, vol. 43, no. 1, pp. 2–12, 2002.

G. F. Lewis and D. J. Rader, “New insights into the regulation of HDL metabolism and reverse cholesterol transport,” Circulation Research, vol. 96, no. 12, pp. 1221–1232, 2005.

Y. Zhang, J. J. Repa, K. Gauthier, and D. J. Mangelsdorf, “Regulation of lipoprotein lipase by the oxysterol receptors, LXRα and LXRβ,” Journal of Biological Chemistry, vol. 276, no. 46, pp. 43018–43024, 2001.

J. J. Repa, S. D. Turley, J. M. A. Lobaccaro et al., “Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers,” Science, vol. 289, no. 5484, pp. 1524–1529, 2000.

J. Y. L. Chiang, R. Kimmel, and D. Stroup, “Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRα),” Gene, vol. 262, no. 1-2, pp. 257–265, 2001.

T. T. Lu, M. Makishima, J. J. Repa et al., “Molecular basis for feedback regulation of bile acid synthesis by nuclear receptos,” Molecular Cell, vol. 6, no. 3, pp. 507–515, 2000.

B. A. Laffitte, J. J. Repa, S. B. Joseph et al., “LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 2, pp. 507–512, 2001.

Y. Luo and A. R. Tall, “Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element,” Journal of Clinical Investigation, vol. 105, no. 4, pp. 513–520, 2000.

J. Y. Cha and J. J. Repa, “The liver X receptor (LXR) and hepatic lipogenesis: the carbohydrate-response element-binding protein is a target gene of LXR,” Journal of Biological Chemistry, vol. 282, no. 1, pp. 743–751, 2007.

T. Inaba, M. Matsuda, M. Shimamura et al., “Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by the liver X receptor,” Journal of Biological Chemistry, vol. 278, no. 24, pp. 21344–21351, 2003.

H. Jakel, M. Nowak, E. Moitrot et al., “The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c,” Journal of Biological Chemistry, vol. 279, no. 44, pp. 45462–45469, 2004.

S. B. Joseph, A. Castrillo, B. A. Laffitte, D. J. Mangelsdorf, and P. Tontonoz, “Reciprocal regulation of inflammation and lipid metabolism by liver X receptors,” Nature Medicine, vol. 9, no. 2, pp. 213–219, 2003.

P. Dandona, A. Aljada, and A. Bandyopadhyay, “Inflammation: the link between insulin resistance, obesity and diabetes,” Trends in Immunology, vol. 25, no. 1, pp. 4–7, 2004.

J. P. Berger, T. E. Akiyama, and P. T. Meinke, “PPARs: therapeutic targets for metabolic disease,” Trends in Pharmacological Sciences, vol. 26, no. 5, pp. 244–251, 2005.

J. Auwerx, E. Baulieu, M. Beato et al., “A unified nomenclature system for the nuclear receptor superfamily,” Cell, vol. 97, no. 2, pp. 161–163, 1999.

B. P. Kota, T. H. W. Huang, and B. D. Roufogalis, “An overview on biological mechanisms of PPARs,” Pharmacological Research, vol. 51, no. 2, pp. 85–94, 2005.

B. Zingarelli, M. Sheehan, P. W. Hake, M. O'Connor, A. Denenberg, and J. A. Cook, “Peroxisome proliferator activator receptor-γ ligands, 15-deoxy-Δ12,14-prostaglandin J2 and ciglitazone, reduce systemic inflammation in polymicrobial sepsis by modulation of signal transduction pathways,” Journal of Immunology, vol. 171, no. 12, pp. 6827–6837, 2003.

S. Yu and J. K. Reddy, “Transcription coactivators for peroxisome proliferator-activated receptors,” Biochimica et Biophysica Acta, vol. 1771, no. 8, pp. 936–951, 2007.

T. Hashimoto, W. S. Cook, C. Qi, A. V. Yeldandi, J. K. Reddy, and M. S. Rao, “Defect in peroxisome proliferator-activated receptor α-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting,” Journal of Biological Chemistry, vol. 275, no. 37, pp. 28918–28928, 2000.

S. Kersten, J. Seydoux, J. M. Peters, F. J. Gonzalez, B. Desvergne, and W. Wahli, “Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting,” Journal of Clinical Investigation, vol. 103, no. 11, pp. 1489–1498, 1999.

R. Hess, W. Stäubli, and W. Riess, “Nature of the hepatomegalic effect produced by ethyl-chlorophenoxy- isobutyrate in the rat,” Nature, vol. 208, no. 5013, pp. 856–858, 1965.

C. Qi, Y. Zhu, and J. K. Reddy, “Peroxisome proliferator-activated receptors, coactivators, and downstream targets,” Cell Biochemistry and Biophysics, vol. 32, pp. 187–204, 2000.

M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998.

N. Latruffe and J. Vamecq, “Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism,” Biochimie, vol. 79, no. 2-3, pp. 81–94, 1997.

G. Martin, H. Poirier, N. Hennuyer et al., “Induction of the fatty acid transport protein 1 and acyl-CoA synthase genes by dimer-selective rexinoids suggests that the peroxisome proliferator- activated receptor-retinoid X receptor heterodimer is their molecular target,” Journal of Biological Chemistry, vol. 275, no. 17, pp. 12612–12618, 2000.

S. Fourcade, S. Savary, S. Albet et al., “Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2): promoter analysis and role of the peroxisome proliferator-activated receptor PPARα,” European Journal of Biochemistry, vol. 268, no. 12, pp. 3490–3500, 2001.

S. É. Michaud and G. Renier, “Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs,” Diabetes, vol. 50, no. 3, pp. 660–666, 2001.

M. S. Rao and J. K. Reddy, “Peroxisomal β-oxidation and steatohepatitis,” Seminars in Liver Disease, vol. 21, no. 1, pp. 43–55, 2001.

S. Yu, K. Matsusue, P. Kashireddy et al., “Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression,” Journal of Biological Chemistry, vol. 278, no. 1, pp. 498–505, 2003.

G. D. Barish, V. A. Narkar, and R. M. Evans, “PPARδ: a dagger in the heart of the metabolic syndrome,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 590–597, 2006.

J. B. Hansen, H. Zhang, T. H. Rasmussen, R. K. Petersen, E. N. Flindt, and K. Kristiansen, “Peroxisome proliferator-activated receptor δ (PPARδ)-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signaling,” Journal of Biological Chemistry, vol. 276, no. 5, pp. 3175–3182, 2001.

M. Schuler, F. Ali, C. Chambon et al., “PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type switching, obesity, and type 2 diabetes,” Cell Metabolism, vol. 4, no. 5, pp. 407–414, 2006.

W. R. Oliver Jr., J. L. Shenk, M. R. Snaith et al., “A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 9, pp. 5306–5311, 2001.

Y. Zhang, H. R. Kast-Woelbern, and P. A. Edwards, “Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation,” Journal of Biological Chemistry, vol. 278, no. 1, pp. 104–110, 2003.

B. M. Forman, E. Goode, J. Chen et al., “Identification of a nuclear receptor that is activated by farnesol metabolites,” Cell, vol. 81, no. 5, pp. 687–693, 1995.

W. Seol, H. S. Choi, and D. D. Moore, “Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors,” Molecular Endocrinology, vol. 9, no. 1, pp. 72–85, 1995.

N. Y. Kalaany and D. J. Mangelsdorf, “LXRs and FXR: the Yin and Yang of cholesterol and fat metabolism,” Annual Review of Physiology, vol. 68, pp. 159–191, 2006.

M. Makishima, A. Y. Okamoto, J. J. Repa et al., “Identification of a nuclear receptor for bite acids,” Science, vol. 284, no. 5418, pp. 1362–1365, 1999.

D. J. Parks, S. G. Blanchard, R. K. Bledsoe et al., “Bile acids: natural ligands for an orphan nuclear receptor,” Science, vol. 284, no. 5418, pp. 1365–1368, 1999.

Y. Zhang, L. W. Castellani, C. J. Sinal, F. J. Gonzalez, and P. A. Edwards, “Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR,” Genes and Development, vol. 18, no. 2, pp. 157–169, 2004.

A. Sirvent, T. Claudel, G. Martin et al., “The farnesoid X receptor induces very low density lipoprotein receptor gene expression,” FEBS Letters, vol. 566, no. 1–3, pp. 173–177, 2004.

G. Lambert, M. J. A. Amar, G. Guo, H. B. Brewer Jr., F. J. Gonzalez, and C. J. Sinal, “The farnesoid X-receptor is an essential regulator of cholesterol homeostasis,” Journal of Biological Chemistry, vol. 278, no. 4, pp. 2563–2570, 2003.

F. Y. Lee, H. Lee, M. L. Hubbert, P. A. Edwards, and Y. Zhang, “FXR, a multipurpose nuclear receptor,” Trends in Biochemical Sciences, vol. 31, no. 10, pp. 572–580, 2006.

I. P. Torra, T. Claudel, C. Duval, V. Kosykh, J. C. Fruchart, and B. Staels, “Bile acids induce the expression of the human peroxisome proliferator-activated receptor α gene via activation of the farnesoid X receptor,” Molecular Endocrinology, vol. 17, no. 2, pp. 259–272, 2003.

B. Cariou, K. van Harmelen, D. Duran-Sandoval et al., “The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice,” Journal of Biological Chemistry, vol. 281, no. 16, pp. 11039–11049, 2006.

M. S. Kim, J. Shigenaga, A. Moser, K. Feingold, and C. Grunfeld, “Repression of farnesoid X receptor during the acute phase response,” Journal of Biological Chemistry, vol. 278, no. 11, pp. 8988–8995, 2003.

L. B. Moore, D. J. Parks, S. A. Jones et al., “Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands,” Journal of Biological Chemistry, vol. 275, no. 20, pp. 15122–15127, 2000.

W. Xie, J. L. Barwick, C. M. Simon et al., “Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR,” Genes and Development, vol. 14, no. 23, pp. 3014–3023, 2000.

P. Wei, J. Zhang, D. H. Dowhan, Y. Han, and D. D. Moore, “Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response,” Pharmacogenomics Journal, vol. 2, no. 2, pp. 117–126, 2002.

J. T. Moore, L. B. Moore, J. M. Maglich, and S. A. Kliewer, “Functional and structural comparison of PXR and CAR,” Biochimica et Biophysica Acta, vol. 1619, no. 3, pp. 235–238, 2003.

S. A. Kliewer, B. Goodwin, and T. M. Willson, “The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism,” Endocrine Reviews, vol. 23, no. 5, pp. 687–702, 2002.

J. Chianale, L. Mulholland, P. G. Traber, and J. J. Gumucio, “Phenobarbital induction of cytochrome P-450 b,e genes is dependent on protein synthesis,” Hepatology, vol. 8, no. 2, pp. 327–331, 1988.

P. G. Quinn and D. Yeagley, “Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulation,” Current Drug Targets: Immune, Endocrine and Metabolic Disorders, vol. 5, no. 4, pp. 423–437, 2005.

J. Nakae, T. Kitamura, D. L. Silver, and D. Accili, “The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression,” Journal of Clinical Investigation, vol. 108, no. 9, pp. 1359–1367, 2001.

S. Kakizaki, Y. Yamazaki, D. Takizawa, and M. Negishi, “New insights on the xenobiotic-sensing nuclear receptors in liver diseases- CAR and PXR-,” Current Drug Metabolism, vol. 9, no. 7, pp. 614–621, 2008.

M. Qatanani, J. Zhang, and D. D. Moore, “Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism,” Endocrinology, vol. 146, no. 3, pp. 995–1002, 2005.

X. Ma, J. R. Idle, and F. J. Gonzalez, “The pregnane X receptor: from bench to bedside,” Expert Opinion on Drug Metabolism and Toxicology, vol. 4, no. 7, pp. 895–908, 2008.

A. Moreau, M. J. Vilarem, P. Maurel, and J. M. Pascussi, “Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory response,” Molecular Pharmaceutics, vol. 5, no. 1, pp. 35–41, 2008.

H. L. Jung, J. Zhou, and W. Xie, “PXR and LXR in hepatic steatosis: a new dog and an old dog with new tricks,” Molecular Pharmaceutics, vol. 5, no. 1, pp. 60–66, 2008.

Y. Konno, M. Negishi, and S. Kodama, “The roles of nuclear receptors CAR and PXR in hepatic energy metabolism,” Drug Metabolism and Pharmacokinetics, vol. 23, no. 1, pp. 8–13, 2008.

A. Roth, R. Looser, M. Kaufmann et al., “Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression,” Molecular Pharmacology, vol. 73, no. 4, pp. 1282–1289, 2008.

R. K. Semple, V. K. K. Chatterjee, and S. O'Rahilly, “PPARγ and human metabolic disease,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 581–589, 2006.

J. Zhou, Y. Zhai, Y. Mu et al., “A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway,” Journal of Biological Chemistry, vol. 281, no. 21, pp. 15013–15020, 2006.

A. Kassam, C. J. Winrow, F. Fernandez-Rachubinski, J. P. Capone, and R. A. Rachubinski, “The peroxisome proliferator response element of the gene encoding the peroxisomal β-oxidation enzyme enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase is a target for constitutive androstane receptor β/9-cis- retinoic acid receptor-mediated transactivation,” Journal of Biological Chemistry, vol. 275, no. 6, pp. 4345–4350, 2000.

Y. Yamazaki, S. Kakizaki, N. Horiguchi et al., “The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis,” Gut, vol. 56, no. 4, pp. 565–574, 2007.

J. M. Maglich, D. C. Lobe, and J. T. Moore, “The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress,” Journal of Lipid Research, vol. 50, no. 3, pp. 439–445, 2009.

M. Wagner, G. Zollner, and M. Trauner, “Nuclear receptors in liver disease,” Hepatology, vol. 53, no. 3, pp. 1023–1034, 2011.