|Nuclear receptors in nonalcoholic Fatty liver disease.|
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|PMID: 22187655 Owner: NLM Status: In-Data-Review|
|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.|
|Jorge A López-Velázquez; Luis D Carrillo-Córdova; Norberto C Chávez-Tapia; Misael Uribe; Nahum Méndez-Sánchez|
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|Type: Journal Article Date: 2011-12-08|
|Title: Journal of lipids Volume: 2012 ISSN: 2090-3049 ISO Abbreviation: J Lipids Publication Date: 2012|
|Created Date: 2011-12-21 Completed Date: - Revised Date: -|
Medline Journal Info:
|Nlm Unique ID: 101553819 Medline TA: J Lipids Country: Egypt|
|Languages: eng Pagination: 139875 Citation Subset: -|
|Liver Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Colonia Toriello Guerra, 14050 Tlalpan, Mexico City, Mexico.|
|APA/MLA Format Download EndNote Download BibTex|
Journal ID (nlm-ta): J Lipids
Journal ID (publisher-id): JL
Publisher: Hindawi Publishing Corporation
Copyright © 2012 Jorge A. López-Velázquez et al.
Received Day: 16 Month: 8 Year: 2011
Accepted Day: 14 Month: 9 Year: 2011
Print publication date: Year: 2012
Electronic publication date: Day: 8 Month: 12 Year: 2011
Volume: 2012E-location ID: 139875
PubMed Id: 22187655
|Nuclear Receptors in Nonalcoholic Fatty Liver Disease|
|Jorge A. López-Velázquez|
|Luis D. Carrillo-Córdova|
|Norberto C. Chávez-Tapia|
|Liver Research Unit, Medica Sur Clinic & Foundation, Puente de Piedra 150, Colonia Toriello Guerra, 14050 Tlalpan, Mexico City, Mexico
|Correspondence: *Nahum Méndez-Sánchez: email@example.com
[other] Academic Editor: Piero Portincasa
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 . 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 .
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 . 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.
NAFLD is defined by the accumulation of triglycerides in the form of droplets (micro- and macrovesicles) within hepatocytes . 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 .
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 . 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 . 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 .
New knowledge about the functions of NRs helps clarify the pathogenesis and pathophysiology of a wide spectrum of hepatic disorders (see Table 1).
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)).
NRs act in three steps : 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  (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 .
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 .
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 .
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 .
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 .
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 .
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 .
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 . LXR positively regulates several enzymes involved in lipoprotein metabolism including lipoprotein lipase (LPL), human cholesteryl ester transport protein, and the phospholipid transfer protein . 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].
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 . 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) , 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 . 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 .
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.
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 .
The PPARs are nuclear hormone receptors. Three isotypes have been identified in humans: PPARα, PPARβ/δ, and PPARγ . 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 .
The role of PPARα in hepatic fatty acid metabolism is especially prominent during fasting. In fasted PPARα-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 .
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.
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 . 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.
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 . 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 . 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 .
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  that normally function as inhibitors of LPL. Finally, the FXR induces human PPARα , 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 . 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 .
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 . 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 . 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 . PXR may also promote hepatic steatosis by increasing the expression of CD36 directly or indirectly through the PXR-mediated activation of PPARγ .
Interestingly, an independent study showed that hepatic triglyceride level decreases temporarily after short-term (10-hour) activation of the PXR . PXR activation is also associated with upregulation of PPARγ, a positive regulator of CD36 and a master regulator of adipogenesis . PXR activation is also associated with suppression of several genes involved in fatty acid β-oxidation, such as PPARα and thiolase . 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).
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 .
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  (Figure 3).
Finally, other studies indicate that the CAR might be involved in the pathogenesis of NASH  by regulating the response of serum triglyceride level to metabolic stress . 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.
NAFLD encompasses a spectrum of conditions characterized histologically by hepatic steatosis ranging from simple fatty liver to NASH cirrhosis and HCC .
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 . 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.
This study was supported by grant from the Mexican National Research Council (CONACYT 62460) and from Medica Sur Clinic & Foundation.
|1.||Méndez-Sánchez N,García-Villegas E,Merino-Zeferino B,et al. Liver diseases in Mexico and their associated mortality trends from 2000 to 2007: a retrospective study of the nation and the federal statesAnnals of HepatologyYear: 20109442843821057162|
|2.||Méndez-Sánchez N,Villa AR,Chávez-Tapia NC,et al. Trends in liver disease prevalence in Mexico from 2005 to 2050 through mortality dataAnnals of HepatologyYear: 200541525515798662|
|3.||Méndez-Sánchez N,Chávez-Tapia NC,Uribe M. Obesity and non-alcoholic steatohepatitisGaceta Medica de MexicoYear: 2004140supplement 2S67S72|
|4.||Farrell GC,Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosisHepatologyYear: 2006432S99S11216447287|
|5.||Chavez-Tapia NC,Méndez-Sánchez N,Uribe M. Role of nonalcoholic fatty liver disease in hepatocellular carcinomaAnnals of HepatologyYear: 20098supplement 1S34S3919381122|
|6.||Méndez-Sánchez N,Arrese M,Zamora-Valdés D,Uribe M. Current concepts in the pathogenesis of nonalcoholic fatty liver diseaseLiver InternationalYear: 200727442343317403181|
|7.||Adiels M,Taskinen MR,Packard C,et al. Overproduction of large VLDL particles is driven by increased liver fat content in manDiabetologiaYear: 200649475576516463046|
|8.||Méndez-Sánchez N,Chavez-Tapia NC,Zamora-Valdés D,Uribe M. Adiponectin, structure, function and pathophysiological implications in non-alcoholic fatty liver diseaseMini-Reviews in Medicinal ChemistryYear: 20066665165616787375|
|9.||Matteoni CA,Younossi ZM,Gramlich T,Boparai N,Liu YC,McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severityGastroenterologyYear: 199911661413141910348825|
|10.||Robinson-Rechavi M,Garcia HE,Laudet V. The nuclear receptor superfamilyJournal of Cell ScienceYear: 2003116458558612538758|
|11.||Lee CH,Wei LN. Characterization of an inverted repeat with a zero spacer (IRO)-type retinoic acid response element from the mouse nuclear orphan receptor TR2-11 geneBiochemistryYear: 199938278820882510393558|
|12.||Mangelsdorf DJ,Thummel C,Beato M,et al. The nuclear receptor super-family: the second decadeCellYear: 19958368358398521507|
|13.||Mangelsdorf DJ,Evans RM. The RXR heterodimers and orphan receptorsCellYear: 19958368418508521508|
|14.||Lonard DM,O’Malley BW. The expanding cosmos of nuclear receptor coactivatorsCellYear: 2006125341141416678083|
|15.||Beato M. Transcriptional control by nuclear receptorsFASEB JournalYear: 199157204420512010057|
|16.||Gronemeyer H,Gustafsson JA,Laudet V. Principles for modulation of the nuclear receptor superfamilyNature Reviews Drug DiscoveryYear: 2004311950964|
|17.||Lonard DM,Lanz RB,O’Malley BW. Nuclear receptor coregulators and human diseaseEndocrine ReviewsYear: 200728557558717609497|
|18.||Karpen SJ. Nuclear receptor regulation of hepatic functionJournal of HepatologyYear: 200236683285012044537|
|19.||Arrese M,Karpen SJ. Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseasesClinical Pharmacology and TherapeuticsYear: 201087447347820200515|
|20.||Lu TT,Repa JJ,Mangelsdorf DJ. Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolismJournal of Biological ChemistryYear: 200127641377353773811459853|
|21.||Willy PJ,Umesono K,Ong ES,Evans RM,Heyman RA,Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathwayGenes and DevelopmentYear: 199599103310457744246|
|22.||Joseph SB,Laffitte BA,Patel PH,et al. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptorsJournal of Biological ChemistryYear: 200227713110191102511790787|
|23.||Horton JD,Goldstein JL,Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liverJournal of Clinical InvestigationYear: 200210991125113111994399|
|24.||Repa JJ,Liang G,Ou J,et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβGenes and DevelopmentYear: 200014222819283011090130|
|25.||Castrillo A,Tontonoz P. Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammationAnnual Review of Cell and Developmental BiologyYear: 200420455480|
|26.||Chen JD,Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptorsNatureYear: 199537765484544577566127|
|27.||Glass CK,Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptorsGenes and DevelopmentYear: 200014212114110652267|
|28.||Edwards PA,Kast HR,Anisfeld AM. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasisJournal of Lipid ResearchYear: 200243121211792716|
|29.||Lewis GF,Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transportCirculation ResearchYear: 200596121221123215976321|
|30.||Zhang Y,Repa JJ,Gauthier K,Mangelsdorf DJ. Regulation of lipoprotein lipase by the oxysterol receptors, LXRα and LXRβJournal of Biological ChemistryYear: 200127646430184302411562371|
|31.||Repa JJ,Turley SD,Lobaccaro JMA,et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimersScienceYear: 200028954841524152910968783|
|32.||Chiang JYL,Kimmel R,Stroup D. Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRα)GeneYear: 20012621-225726511179691|
|33.||Lu TT,Makishima M,Repa JJ,et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptosMolecular CellYear: 20006350751511030331|
|34.||Laffitte BA,Repa JJ,Joseph SB,et al. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytesProceedings of the National Academy of Sciences of the United States of AmericaYear: 200198250751211149950|
|35.||Luo Y,Tall AR. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR elementJournal of Clinical InvestigationYear: 2000105451352010683381|
|36.||Cha JY,Repa JJ. The liver X receptor (LXR) and hepatic lipogenesis: the carbohydrate-response element-binding protein is a target gene of LXRJournal of Biological ChemistryYear: 2007282174375117107947|
|37.||Inaba T,Matsuda M,Shimamura M,et al. Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by the liver X receptorJournal of Biological ChemistryYear: 200327824213442135112672813|
|38.||Jakel H,Nowak M,Moitrot E,et al. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1cJournal of Biological ChemistryYear: 200427944454624546915317819|
|39.||Joseph SB,Castrillo A,Laffitte BA,Mangelsdorf DJ,Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptorsNature MedicineYear: 200392213219|
|40.||Dandona P,Aljada A,Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetesTrends in ImmunologyYear: 20042514714698276|
|41.||Berger JP,Akiyama TE,Meinke PT. PPARs: therapeutic targets for metabolic diseaseTrends in Pharmacological SciencesYear: 200526524425115860371|
|42.||Auwerx J,Baulieu E,Beato M,et al. A unified nomenclature system for the nuclear receptor superfamilyCellYear: 199997216116310219237|
|43.||Kota BP,Huang THW,Roufogalis BD. An overview on biological mechanisms of PPARsPharmacological ResearchYear: 2005512859415629253|
|44.||Zingarelli B,Sheehan M,Hake PW,O’Connor M,Denenberg A,Cook JA. 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 pathwaysJournal of ImmunologyYear: 20031711268276837|
|45.||Yu S,Reddy JK. Transcription coactivators for peroxisome proliferator-activated receptorsBiochimica et Biophysica ActaYear: 20071771893695117306620|
|46.||Hashimoto T,Cook WS,Qi C,Yeldandi AV,Reddy JK,Rao MS. Defect in peroxisome proliferator-activated receptor α-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fastingJournal of Biological ChemistryYear: 200027537289182892810844002|
|47.||Kersten S,Seydoux J,Peters JM,Gonzalez FJ,Desvergne B,Wahli W. Peroxisome proliferator-activated receptor α mediates the adaptive response to fastingJournal of Clinical InvestigationYear: 1999103111489149810359558|
|48.||Hess R,Stäubli W,Riess W. Nature of the hepatomegalic effect produced by ethyl-chlorophenoxy- isobutyrate in the ratNatureYear: 196520850138568585870099|
|49.||Qi C,Zhu Y,Reddy JK. Peroxisome proliferator-activated receptors, coactivators, and downstream targetsCell Biochemistry and BiophysicsYear: 20003218720411330046|
|50.||Ricote M,Li AC,Willson TM,Kelly CJ,Glass CK. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activationNatureYear: 1998391666279829422508|
|51.||Latruffe N,Vamecq J. Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolismBiochimieYear: 1997792-381949209701|
|52.||Martin G,Poirier H,Hennuyer N,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 targetJournal of Biological ChemistryYear: 200027517126121261810777552|
|53.||Fourcade S,Savary S,Albet S,et al. Fibrate induction of the adrenoleukodystrophy-related gene (ABCD2): promoter analysis and role of the peroxisome proliferator-activated receptor PPARαEuropean Journal of BiochemistryYear: 2001268123490350011422379|
|54.||Michaud SÉ,Renier G. Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARsDiabetesYear: 200150366066611246888|
|55.||Rao MS,Reddy JK. Peroxisomal β-oxidation and steatohepatitisSeminars in Liver DiseaseYear: 2001211435511296696|
|56.||Yu S,Matsusue K,Kashireddy P,et al. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpressionJournal of Biological ChemistryYear: 2003278149850512401792|
|57.||Barish GD,Narkar VA,Evans RM. PPARδ: a dagger in the heart of the metabolic syndromeJournal of Clinical InvestigationYear: 2006116359059716511591|
|58.||Hansen JB,Zhang H,Rasmussen TH,Petersen RK,Flindt EN,Kristiansen K. Peroxisome proliferator-activated receptor δ (PPARδ)-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signalingJournal of Biological ChemistryYear: 200127653175318211069900|
|59.||Schuler M,Ali F,Chambon C,et al. PGC1α expression is controlled in skeletal muscles by PPARβ, whose ablation results in fiber-type switching, obesity, and type 2 diabetesCell MetabolismYear: 20064540741417084713|
|60.||Oliver WR Jr.,Shenk JL,Snaith MR,et al. A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transportProceedings of the National Academy of Sciences of the United States of AmericaYear: 20019895306531111309497|
|61.||Zhang Y,Kast-Woelbern HR,Edwards PA. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activationJournal of Biological ChemistryYear: 2003278110411012393883|
|62.||Forman BM,Goode E,Chen J,et al. Identification of a nuclear receptor that is activated by farnesol metabolitesCellYear: 19958156876937774010|
|63.||Seol W,Choi HS,Moore DD. Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptorsMolecular EndocrinologyYear: 19959172857760852|
|64.||Kalaany NY,Mangelsdorf DJ. LXRs and FXR: the Yin and Yang of cholesterol and fat metabolismAnnual Review of PhysiologyYear: 200668159191|
|65.||Makishima M,Okamoto AY,Repa JJ,et al. Identification of a nuclear receptor for bite acidsScienceYear: 199928454181362136510334992|
|66.||Parks DJ,Blanchard SG,Bledsoe RK,et al. Bile acids: natural ligands for an orphan nuclear receptorScienceYear: 199928454181365136810334993|
|67.||Zhang Y,Castellani LW,Sinal CJ,Gonzalez FJ,Edwards PA. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXRGenes and DevelopmentYear: 200418215716914729567|
|68.||Sirvent A,Claudel T,Martin G,et al. The farnesoid X receptor induces very low density lipoprotein receptor gene expressionFEBS LettersYear: 20045661–317317715147890|
|69.||Lambert G,Amar MJA,Guo G,Brewer HB Jr.,Gonzalez FJ,Sinal CJ. The farnesoid X-receptor is an essential regulator of cholesterol homeostasisJournal of Biological ChemistryYear: 200327842563257012421815|
|70.||Lee FY,Lee H,Hubbert ML,Edwards PA,Zhang Y. FXR, a multipurpose nuclear receptorTrends in Biochemical SciencesYear: 2006311057258016908160|
|71.||Torra IP,Claudel T,Duval C,Kosykh V,Fruchart JC,Staels B. Bile acids induce the expression of the human peroxisome proliferator-activated receptor α gene via activation of the farnesoid X receptorMolecular EndocrinologyYear: 200317225927212554753|
|72.||Cariou B,van Harmelen K,Duran-Sandoval D,et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in miceJournal of Biological ChemistryYear: 200628116110391104916446356|
|73.||Kim MS,Shigenaga J,Moser A,Feingold K,Grunfeld C. Repression of farnesoid X receptor during the acute phase responseJournal of Biological ChemistryYear: 2003278118988899512519762|
|74.||Moore LB,Parks DJ,Jones SA,et al. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligandsJournal of Biological ChemistryYear: 200027520151221512710748001|
|75.||Xie W,Barwick JL,Simon CM,et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CARGenes and DevelopmentYear: 200014233014302311114890|
|76.||Wei P,Zhang J,Dowhan DH,Han Y,Moore DD. Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic responsePharmacogenomics JournalYear: 20022211712612049174|
|77.||Moore JT,Moore LB,Maglich JM,Kliewer SA. Functional and structural comparison of PXR and CARBiochimica et Biophysica ActaYear: 20031619323523812573482|
|78.||Kliewer SA,Goodwin B,Willson TM. The nuclear pregnane X receptor: a key regulator of xenobiotic metabolismEndocrine ReviewsYear: 200223568770212372848|
|79.||Chianale J,Mulholland L,Traber PG,Gumucio JJ. Phenobarbital induction of cytochrome P-450 b,e genes is dependent on protein synthesisHepatologyYear: 1988823273313356413|
|80.||Quinn PG,Yeagley D. Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulationCurrent Drug Targets: Immune, Endocrine and Metabolic DisordersYear: 200554423437|
|81.||Nakae J,Kitamura T,Silver DL,Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expressionJournal of Clinical InvestigationYear: 200110891359136711696581|
|82.||Kakizaki S,Yamazaki Y,Takizawa D,Negishi M. New insights on the xenobiotic-sensing nuclear receptors in liver diseases- CAR and PXR-Current Drug MetabolismYear: 20089761462118781913|
|83.||Qatanani M,Zhang J,Moore DD. Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolismEndocrinologyYear: 20051463995100215564320|
|84.||Ma X,Idle JR,Gonzalez FJ. The pregnane X receptor: from bench to bedsideExpert Opinion on Drug Metabolism and ToxicologyYear: 20084789590818624678|
|85.||Moreau A,Vilarem MJ,Maurel P,Pascussi JM. Xenoreceptors CAR and PXR activation and consequences on lipid metabolism, glucose homeostasis, and inflammatory responseMolecular PharmaceuticsYear: 200851354118159929|
|86.||Jung HL,Zhou J,Xie W. PXR and LXR in hepatic steatosis: a new dog and an old dog with new tricksMolecular PharmaceuticsYear: 200851606618072748|
|87.||Konno Y,Negishi M,Kodama S. The roles of nuclear receptors CAR and PXR in hepatic energy metabolismDrug Metabolism and PharmacokineticsYear: 200823181318305370|
|88.||Roth A,Looser R,Kaufmann M,et al. Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expressionMolecular PharmacologyYear: 20087341282128918187584|
|89.||Semple RK,Chatterjee VKK,O’Rahilly S. PPARγ and human metabolic diseaseJournal of Clinical InvestigationYear: 2006116358158916511590|
|90.||Zhou J,Zhai Y,Mu Y,et al. A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathwayJournal of Biological ChemistryYear: 200628121150131502016556603|
|91.||Kassam A,Winrow CJ,Fernandez-Rachubinski F,Capone JP,Rachubinski RA. 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 transactivationJournal of Biological ChemistryYear: 200027564345435010660604|
|92.||Yamazaki Y,Kakizaki S,Horiguchi N,et al. The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitisGutYear: 200756456557416950832|
|93.||Maglich JM,Lobe DC,Moore JT. The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stressJournal of Lipid ResearchYear: 200950343944518941143|
|94.||Wagner M,Zollner G,Trauner M. Nuclear receptors in liver diseaseHepatologyYear: 20115331023103421319202|
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