The nuclear receptor FXR, but not LXR, up-regulates bile acid transporter expression in non-alcoholic fatty liver disease
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1 ORIGINAL ARTICLE July-August, Vol. 14 No. 4, 2015: The nucler receptor FXR, but not LXR, up-regultes bile cid trnsporter expression in non-lcoholic ftty liver disese Nncy E. Aguilr-Olivos, Dniel Crrillo-Córdov, Jesús Ori-Hernández, Vicente Sánchez-Vlle, Gudlupe Poncino-Rodríguez, Mnuel Rmírez-Jrmillo, Fredy Chblé-Montero, Norberto C. Chávez-Tpi, Misel Uribe, Nhum Méndez-Sánchez Liver Reserch Unit, Medic Sur Clinic & Foundtion, Mexico City, Mexico. Biochemistry nd Genetics Lb, Ntionl Institute of Peditrics, Ministry of Helth, Mexico City, Mexico. Public Helth Deprtment, Fculty of Medicine, Ntionl Autonomous University of Mexico, Mexico City, Mexico. Pthology Deprtment, Medic Sur Clinic & Foundtion, Mexico City, Mexico. ABSTRACT Bckground. Non-lcoholic ftty liver disese (NAFLD) is the most common cuse of chronic liver disese. Ptients with non-lcoholic stetoheptitis (NASH) hve incresed plsmtic nd heptic concentrtions of bile cids (BA), suggesting tht they cn be ssocited with the progression of the disese. Heptic nucler receptors re known to modulte genes controlling BA metbolism; thus, in this work we imed to compre the expression of liver nucler receptors frnesoid X (FXR), smll heterodimer prtner (SHP) nd liver X lph (LXRα) receptors nd BA trnsporters sodium+/turocholte cotrnsporting polypeptide (NTCP) nd bile slt export pump (BSEP) in liver biopsy smples of ptients with simple stetosis (SS) nd NASH. Mteril nd methods. Forty ptients with biopsy-proven NALFD were enrolled between 2009 nd 2012; liver biopsies were clssified s SS (N = 20) or NASH (N = 20) ccording to the NAFLD ctivity score. Gene expression of nucler FXR, LXRα, SHP, NTCP nd BSEP ws nlyzed by rel-time reverse trnscription polymerse chin rection nd protein level ws quntified by western blot. Results. Gene expression of FXR, SHP, NTCP nd BSEP ws significntly up-regulted in the NASH group in comprison with SS ptients (P < 0.05). In contrst, protein level for FXR, SHP nd NTCP ws decresed in the NASH ptients vs. the SS group (P < 0.05). Gene nd protein profile of LXRα did not show differences between groups. Conclusions. The results suggest tht liver nucler receptors (FXR nd SHP) nd BA trnsporters (NTCP nd BSEP) re ssocited with the progression of NAFLD. Key words. Ftty liver. Assocition. Nucler receptors. INTRODUCTION Non-lcoholic ftty liver disese (NAFLD) encompsses spectrum of heptic pthologies rnging, including simple stetosis (SS) nd non-lcoholic stetoheptitis (NASH). 1 NASH cn progress to fibrosis, cirrhosis, liver filure nd heptocellulr crcinom. 2 At present time, NAFLD is considered the most common cuse of chronic liver disese nd it is mjor public helth issue. 3,4 The prevlence of Correspondence nd reprint request: Prof. Nhum Méndez-Sánchez, MD, MSc, PhD, FACG, AGAF Liver Reserch Unit, Medic Sur Clinic & Foundtion. Puente de Piedr 150, Col. Toriello Guerr, ZP 14050, Mexico City, Mexico. Ph.: (+5255) Ext Fx: (+5255) E-mil: nmendez@medicsur.org.mx Mnuscript received: November 10, Mnuscript ccepted: December 2, NAFLD in the generl popultion is round 20%, but certin groups, including ptients with type-2 dibetes mellitus, obesity, dyslipidemi, nd metbolic syndrome, re t higher risk for developing NAFLD. 5-7 In fct, glucose nd lipid metbolism disturbnces hve been clerly implicted s min underlying fctors for NAFLD development. 8 The Frnesoid X receptor (FXR), member of the lignd-ctivted nucler receptor trnscription fctors superfmily, hs gined importnce s pthogenic fctor in NAFLD; it hs been shown tht this receptor modultes number of criticl genes implicted in the homeostsis of glucose, the metbolism of lipids nd bile cids (BA), s well s the immune response. 9,10 It hs been shown tht BA cn modify these metbolic pthwys through FXR modultion Therefore, FXR ctivity nd BA homeostsis re currently considered s key plyers in the regultion of generl metbolism, energy expenditure
2 488 Aguilr-Olivos N, et l., 2015; 14 (4): nd inflmmtory processes. 9 In this connection, it is noteworthy tht NASH ptients hve incresed levels of BA, both in plsm nd liver tissue, 14 suggesting n ssocition between the presence of toxic levels of BA nd the development of the disese; 15 thus, understnding the contribution of nucler receptors nd BA dysregultion to the pthogenesis nd progression of NAFLD is centrl issue in heptology BA metbolism genes under regultion of FXR include the nucler receptor smll heterodimer prtner 17 (SHP, NR0B2), the sodium/turocholte cotrnsporting polypeptide (NTCP, SLC10A1), cholesterol 7α-hydroxylse (CYP7A1), nd the bile slt export pump (BSEP, ABCB11). 18,19 In ddition, Liver X receptor lph (LXRα, NR1H3) hs lso been implicted in the pthogenesis of NAFLD. LXRα is nucler receptor involved in the modultion of cholesterol metbolism nd heptic free cids biosynthesis whose expression hs been found ltered in NAFLD ptients. 20,21 In this work, we imed to compre the expression of liver nucler receptors (FXR, LXRα nd SHP) nd BA trnsporters (NTCP nd BSEP) in liver biopsy smples of ptients with SS nd NASH. We hypothesized tht NASH ptients could disply differentil gene nd protein expression profile when compred with SS ptients, nd tht such differences could help to increse our understnding of NAFLD progression. MATERIAL AND METHODS Study design This is descriptive study, designed for evlution of gene nd protein expression of components of intrheptic BA metbolism, including FXR, LXRα, SHP, NTCP nd BSEP. Ptients Forty ptients with biopsy-proven NAFLD were enrolled in the study t the Liver Reserch Unit of the Medic Sur Clinic & Foundtion over the period from 2009 to For ech ptient, demogrphic, clinicl, nd biochemicl vribles were recorded. Exclusion criteri included ge younger thn 18 or older thn 65, history of liver injuries nd infective pthologies (heptitis B, heptitis C, or humn immunodeficiency), orgn trnsplnttion, mlignncy, utoimmunity, genetic disorders, therpy with immunosuppressive gents or excessive lcohol consumption (> 10 g/dy in women nd > 20 g/dy in men). Informed written consent ws obtined from ll subjects for use of clinicl nd tissue mterils for reserch purposes. Ethics sttement The study protocol complied with the ethicl guidelines of the 1975 Declrtion of Helsinki nd ws pproved by the Ethics Committee (Comité de Étic en Investigción de Médic Sur, S.A.B. de C.V.) of our hospitl. Humn smple preprtion nd processing Biopsy specimens were formlin fixed, sectioned, nd stined with hemtoxylin nd eosin nd Msson s trichrome. The NAFLD ctivity score, NAS, ws used for the histologicl ssessment of NAFLD. 22 Ptients who hd NAS < 4 were considered to hve SS; NASH ws defined s the presence of stetosis, lobulr inflmmtion, nd bllooning degenertion with or without Mllory-Denk bodies, nd with or without fibrosis (NAS 4). RNA isoltion nd reverse trnscription-quntittive polymerse chin rection (RT-qPCR) nlysis Totl RNA ws extrcted from liver biopsies by using the RNesy FFPE Kit (Qigen). The RNA Tble 1. Sequences of oligonucleotides employed in RT-qPCR ssys. Gene FXR LXR-α SHP BSEP NTCP UBQ HMBS Sequence F: 5 -ACAGAACAAGTGGCAGGTC-3 R: 5 -CTGAAGAAACCTTTACACCCCTC-3 F: 5 -GAAGAAACTGAAGCGGCAAGA-3 R: 5 -ACTCGAAGCCGGTCAGAAAA-3 F: 5 -GGCTTCAATGCTGTCTGGAGT-3 R: 5 -CTGGCACATCGGGGTTGAAGA-3 F: 5 -GGAACCAGTGTTGTTTGCCT-3 R: 5 -AAAATCATGCAGCTGAGCCT-3 F: 5 -CCCAAGAAGCCTCACCTATC-3 R: 5 -TTGGGTCACAAAACTTGGAA-3 F: 5 -CCTGGTGCTCCGTCTTAGAG-3 R: 5 -TTTCCCAGCAAAGATCAACC-3 F: 5 -GGCAATGCGGCTGCAA-3 R: 5 -GGGTACCCACGCGAATCAC-3
3 Nucler receptors nd NAFLD., 2015; 14 (4): purity nd integrity ws corroborted by spectrophotometry (260/280 rtio) nd electrophoresis (grose gel 1 %). RT-qPCR ssys were performed in CFX96 Rel-Time PCR Detection System (Bio-Rd, Hercules, CA). Trgets RNAs were quntified with the QuntiTect SYBR Green RT qpcr Kit (Qigen). Gene-specific primer, tble 1, were designed nd synthesized t the Unidd de Biologí Moleculr of the Instituto de Fisiologí Celulr on the Universidd Ncionl Autónom de México. One step RT qpcr ws conducted with reverse trnscription t 50 C for 30 min, denturtion t 95 C for 15 min nd 40 cycles t 94 C for 15 s, 55 C for 30 s, nd 72 C for 30 s. The specificity of gene mplifiction ws confirmed by independent end-point PCR nlysis. The gene expression dt re presented s reltive gene expression using ubiquitin C (UBC) nd hydroxymethylbilne synthse (HMBS) s endogenous RNAs reference; UBC nd HMBS re been found to be the most ccurte normliztion fctors for rel time RT-qPCR nlysis in liver smples. 23 Vlues were collected for the threshold cycle (Ct) for ech gene, nd only Ct vlues less thn 40 were considered for further nlysis; the results shown re the men of duplicte experimentl determintions. Protein extrction nd Western blot nlysis Totl protein ws extrcted from prffin tissue blocks using the protein isoltion Qproteome FFPE Tissue Kit (Qigen). Protein ws quntified by the bicinchoninic cid method using the Micro BCA Protein Assy Kit (Thermo Scientific Pierce), 4-20% SDS-PAGE ws performed in Mini-PROTEAN TGX precst gels with 15 g of totl protein nd electroblotted onto polyvinylidene difluoride membrnes (Bio-Rd). Immunodetection ws performed with nti-fxr, LXRα, SHP, BSEP nd, NTCP (1:250; GeneTex) nd β-ctin (1:20,000; Bio-Rd) monoclonl ntibodies. Got nti-rbbit peroxidse conjugted secondry ntibody (1:20,000; Bio-Rd) nd the Immun-Str WesternC Chemiluminescent Kit (Bio-Rd) were used to visulize protein bnds. Imges were digitized with Gel Doc XR+ System nd densitometriclly nlyzed with the Quntity One softwre (Bio-Rd); protein expression ws normlized with respect to the β-ctin signl. Sttisticl nlysis Dt re given s mens ± stndrd devitions. Sttisticlly significnt differences were ssessed by one-wy nlysis of vrince. If differences were found, vlues were compred using the Student s t- test; P < 0.05 ws considered significnt. Anlyses were performed with SPSS softwre (20.0.1, v. 2012; IBM SPSS). RESULTS Forty NAFLD ptients, 20 clssified s SS nd 20 s NASH ccording to the NAS score, were enrolled Tble 2. Demogrphic nd clinicl dt of NAFLD ptients. Simple stetosis (n = 20) NASH (n = 20) Femle/mle 10/10 8/12 Age (yers) 46.6 ± ±14.02 Weight (kg) ± ± Height (cm) ± ± 0.17 BMI (kg/m 2 ) 26 ± ± 5.74 AST (U/L) 44 ± ± ALT (U/L) 58 ± ± Conjugted bilirubin (mg/dl) 1 ± ± 0.84 Unconjugted bilirubin (mg/dl) 0.9 ± ± 1.01 Totl bilirubin (mg/dl) 1.44 ± ± 1.48 Albumin (g/dl) 4 ± ± 0.84 Totl protein (g/dl) 6 ± ± 1.45 Triglycerides (mg/dl) 199 ± ± Cholesterol (mg/dl) 182 ± ± LDL (mg/dl) 125 ± ± Hemoglobin (g/dl) 14 ± ± 2.70 Pltelets (x 10 6 /μl) 200 ± ± NAFLD: nonlcoholic ftty liver disese. NASH: nonlcoholic stetoheptitis. BMI: body mss index. ALT: lnine minotrnsferse. AST: sprtte minotrnsferse. LDL: low density lipoproteins.
4 490 Aguilr-Olivos N, et l., 2015; 14 (4): in the study. The clinicl nd demogrphic fetures of these ptients re shown in tble 2. Gene expression studies showed tht the FXR mrna levels in the NASH group were significntly higher thn those in the SS group (P < 0.05), in concordnce, overexpression ws observed for SHP (P < 0.05) nd BSEP (P < 0.05). Contrry to expecttions, NTCP ws overexpressed in NASH ptients compred with the SS group (P < 0.05). LXR mrna expression levels were high in both groups, but without significnt differences between them (Figure 1). In regrd to protein expression, it ws found tht FXR ws diminished in NASH ptients compred with SS ptients (P < 0.05), nd the sme behvior ws observed for SHP nd NTCP (P < 0.05 for both). As for the RT-qPCR ssys, LXRα protein expression remined unchnged between both groups (Figure 2). BSEP ws under the limit of detection of Western blot ssys nd could not be further nlyzed. DISCUSSION The results of this work show tht NASH ptients possess different mrna nd protein expression profile of heptic nucler receptors (FXR nd SHP) nd BA trnsporters (NTCP nd BSEP) when compred with SS ptients. It ws found n up-regulted mrna expression of FXR, SHP, NTCP nd BSEP in liver biopsies from ptients with NASH, wheres in contrst, FXR, SHP nd NTCP showed decresed protein content in the sme smples. No sttisticlly significnt differences were detected for LXR gene expression nd protein level between the SS nd NASH groups. It hs been described tht FXR regultes, directly or through the nucler receptor SHP, wide vriety of trget genes criticlly involved in BA metbolism nd lipid nd glucose homeostsis. 9 Regrding BA metbolism, it hs been shown tht ctivted FXR induces the expression of SHP in heptocytes, which in turn blocks the expression of NTCP; 24,25 in ddition, ctivtion of FXR inhibits the synthesis of BA from cholesterol nd decreses its ccumultion in liver. 26 In this connection, it hs been demonstrted tht toxic ccumultion of liver BA is ssocited with fibrosis progression. 27,28 Finlly, niml models of FXR deficiency show the pthologic mnifesttions of NASH, including mcro-stetosis, heptocyte bllooning nd inflmmtion. 29,30 It seems to be cler tht FXR nd its gene trgets ply centrl role on the pthogenesis of NAFLD, but this conclusion Reltive mrna expression SS NASH p < 0.05 LXR-α FXR SHP NTCP BSEP Reltive protein expression p < 0.05 SS NASH LXR-α FXR SHP NTCP Figure 1. Gene expression of nucler receptors nd bile cid trnsporters SS nd NASH liver biopsies. FXR, SHP, NTCP, nd BSEP gene expression ws significntly upregulted in NASH vs. simple stetosis (SS) (P < 0.05), wheres LXRα expression ws not significntly different between NASH nd SS ptients. FXR, frnesoid X receptor; SHP, short heterodimer prtner; NTCP, Sodium+/Turocholte cotrnsporting polypeptide; BSEP, bile slt export pump; LXRα, Liver X receptor lph. Differences were nlyzed by Student s t-test. Figure 2. Protein level of nucler receptors nd bile cid trnsporters in SS nd NASH liver biopsies. Protein expression of FXR, SHP nd NTCP ws significntly diminished in NASH compred with SS ptients (P < 0.05), while LXR protein content remined unchnged between the groups. FXR: frnesoid X receptor. SHP: short heterodimer prtner. NTCP: N+/turocholte cotrnsporting polypeptide. LXRα: liver X receptor lph. Differences were nlyzed by Student s t-test.
5 Nucler receptors nd NAFLD., 2015; 14 (4): rises minly from niml models. 24,26,28,30 In this respect, the dt obtined from ptient biopsies re illustrtive from the humn pthology. In concordnce with the niml model studies, we found low protein level of FXR in liver smples from NASH ptients, which ws prlleled by decresed protein level of SHP nd NTCP (Figure 2). Interestingly, however, corresponding mrna expression of FXR, SHP nd NTCP were elevted in the sme smples (Figure 1). From these results, two points deserve considertion: We detected down-regultion protein expression of FXR, SHP nd NTCP; however, we would expect n up-regultion of NTCP with regrd to puttive negtive feedbck regultion by SHP. This inconsistency could be relted to the known lrge inter-individul vribility of the NTCP expression (even in helthy controls), nd to the high inhibitory effect of BA over NTCP. 31 In ddition, dysfunction in the repression pthwy of SHP hs been recently reported in group of super-obese NASH ptients, 32 which my suggest disturbnce on the regultion of NCTP by SHP in NASH ptients. The pprent discordnce between mrna expression nd protein level for FXR, SHP nd NTCP is intriguing; since mrna is trnslted into proteins; it is generlly ssumed tht protein levels must be correlted to the levels of its corresponding mrnas. However, recent experimentl evidence indictes tht this ssumption my be in mny cses erroneous. 33 For exmple, the correltion between RNA levels nd its corresponding proteins evluted by trnscriptomic (cdna nd oligo microrrys) nd proteomic (immunohistochemistry in tissue microrrys) dt obtined for 23 humn cell lines indictes tht correltion coefficients vry widely; significnt correltion ws found only in one third of the cses, with men correltion coefficient for the totl smple of only ~ Along this line, whole humn proteome dtset bsed on mss spectrometry, 34 ws used to compre the protein expression of 12 tissues with recently published mrna vlues determined by quntittive trnscriptomics nlysis. 35 The results show n verge correltion coefficient of 0.41, indicting gin, generl poor correltion between protein nd mrna levels. In generl, correltion coefficients of ~0.4 hve been found in diverse biologicl systems; 36 this implictes tht most of the time, s in our cse, protein levels my not be proportionl to its mrna. Current dt indictes tht the reltionship between mrna expression nd protein bundnce reflects the dynmic blnce between diverse trnscriptionl nd trnsltionl processes, with min role for regultion occurring fter mrna synthesis (v.g. post-trnscriptionl, trnsltionl nd protein degrdtion regultion) contributing s much s trnscription regultion. 36 In concordnce with the dt obtined in this work, it cn be estblished tht mrna expression chnges my not lwys mtch with chnges in protein levels. The quntifiction of these two mcromolecules is not redundnt if not complementry, nd both re necessry for full description of disese mechnisms. Recently, ltertions in BA trnsport nd metbolism, including under-expression of NTCP nd BSEP genes nd lower protein levels of NTCP, hs been described in morbidly obese NASH ptients, 32 suggesting n importnt role of FXR in the progression of NAFLD. Compred with tht work, lower protein level of NTCP is consistent with our results; however, the results of mrna expression seem opposites. As indicted, these discrepncies could suggest complex post-trnscriptionl mechnisms (low trnsltionl rte or high protein degrdtion, for exmple) regulting the expression of proteins relted to BA trnsport nd metbolism. Despite the differences, the dt in both works support the connection between BA metbolism dysregultion nd NASH development medited by FXR. The present study hs some limittions, including the low number of ptients studied, the lck of quntifiction of CYP7A1 expression nd the fct tht protein level of BSEP could not be evluted. Additionl studies surpssing these limittions nd extending the nlysis of trnscriptionl fctors nd nucler receptors involved in lipid nd BA metbolism nd its regultion mechnisms in ptient smples could increse our understnding of NAFLD progression. CONCLUSIONS This work showed overexpression of FXR, SHP, NTCP, nd BSEP genes wheres protein level of FXR SHP nd NTCP ws decresed in liver smples of NASH ptients compred with SS ptients. Altogether, the results involve to FXR nd its ssocited genes nd metbolic pthwys with
6 492 Aguilr-Olivos N, et l., 2015; 14 (4): the progression from SS to NASH in NAFLD ptients. Future nd complementry studies re required to chrcterize the detiled moleculr mechnisms involved in the regultion of BA metbolism nd its reltionship to NAFLD progression; it is plusible tht this informtion cn contribute to found new therpeutic options for this disese. ABBREVIATIONS BA: bile cids. BSEP: bile slt export pump. CYP7A1: cholesterol 7-hydroxylse. FXR: nucler frnesoid X receptor. HMBS: hydroxymethylbilne synthse. LXRα: nucler liver X receptor. mrna: messenger ribonucleic cid. NAFLD: Non-lcoholic ftty liver disese. NAS: NAFLD ctivity score. NASH: non-lcoholic stetoheptitis. NTCP: sodium/turocholte cotrnsporting polypeptide. RT-qPCR: reverse trnscription-quntittive polymerse chin rection. SDS-PAGE: sodium dodecyl sulfte polycrylmide gel electrophoresis. SHP: smll heterodimer prtner. SS: simple stetosis. UBC: ubiquitin C. FINANCIAL SUPPORT Medic Sur Clinic & Foundtion funded this study. None. CONFLICT OF INTEREST ACKNOWLEDGMENTS Medic Sur Clinic & Foundtion, Mexico City, Mexico. REFERENCES 1. Angulo P. Nonlcoholic ftty liver disese. N Engl J Med 2002; 346: Schuppn D, Schttenberg JM. Non-lcoholic stetoheptitis: pthogenesis nd novel therpeutic pproches. J Gstroenterol Heptol 2013; 28(Suppl. 1): Vernon G, Brnov A, Younossi ZM. Systemtic review: the epidemiology nd nturl history of non-lcoholic ftty liver disese nd non-lcoholic stetoheptitis in dults. Aliment Phrmcol Ther 2011; 34: Lopez-Velzquez JA, Silv-Vidl KV, Poncino-Rodriguez G, Chvez-Tpi NC, Arrese M, Uribe M, Mendez-Snchez N. The prevlence of nonlcoholic ftty liver disese in the Americs. Ann Heptol 2014; 13: Leite NC, Slles GF, Arujo AL, Villel-Nogueir CA, Crdoso CR. Prevlence nd ssocited fctors of non-lcoholic ftty liver disese in ptients with type-2 dibetes mellitus. Liver Int 2009; 29: Gholm PM, Flncbum L, Mchn JT, Chrney DA, Kotler DP. Nonlcoholic ftty liver disese in severely obese subjects. Am J Gstroenterol 2007; 102: Assy N, Kit K, Mymin D, Levy C, Rosser B, Minuk G. Ftty infiltrtion of liver in hyperlipidemic ptients. Dig Dis Sci 2000; 45: Mendez-Snchez N, Arrese M, Zmor-Vldes D, Uribe M. Current concepts in the pthogenesis of nonlcoholic ftty liver disese. Liver Int 2007; 27: Adorini L, Pruznski M, Shpiro D. Frnesoid X receptor trgeting to tret nonlcoholic stetoheptitis. Drug Discov Tody 2012; 17: Li Y, Jdhv K, Zhng Y. Bile cid receptors in non-lcoholic ftty liver disese. Biochem Phrmcol 2013; 86: Lefebvre P, Criou B, Lien F, Kuipers F, Stels B. Role of bile cids nd bile cid receptors in metbolic regultion. Physiol Rev 2009; 89: Hollmn DA, Milon A, vn Erpecum KJ, vn Mil SW. Anti-inflmmtory nd metbolic ctions of FXR: insights into moleculr mechnisms. Biochim Biophys Act 2012; 1821: Pols TW, Norieg LG, Nomur M, Auwerx J, Schoonjns K. The bile cid membrne receptor TGR5 s n emerging trget in metbolism nd inflmmtion. J Heptol 2011; 54: Dsrthy S, Yng Y, McCullough AJ, Mrczewski S, Bennett C, Klhn SC. Elevted heptic ftty cid oxidtion, high plsm fibroblst growth fctor 21, nd fsting bile cids in nonlcoholic stetoheptitis. Eur J Gstroenterol Heptol 2011; 23: Arnh MM, Cortez-Pinto H, Cost A, d Silv IB, Cmilo ME, de Mour MC, Rodrigues CM. Bile cid levels re incresed in the liver of ptients with stetoheptitis. Eur J Gstroenterol Heptol 2008; 20: Truner M, Hlilbsic E. Nucler receptors s new perspective for the mngement of liver diseses. Gstroenterology 2011; 140: e Wgner M, Zollner G, Truner M. Nucler receptors in liver disese. Heptology 2011; 53: Lopez-Velzquez JA, Crrillo-Cordov LD, Chvez-Tpi NC, Uribe M, Mendez-Snchez N. Nucler receptors in nonlcoholic ftty liver disese. J Lipids 2012; 2012: Schp FG, Truner M, Jnsen PL. Bile cid receptors s trgets for drug development. Nt Rev Gstroenterol Heptol 2014; 11: Berlng A, Guiu-Jurdo E, Porrs JA, Auguet T. Moleculr pthwys in non-lcoholic ftty liver disese. Clin Exp Gstroenterol 2014; 7: Higuchi N, Kto M, Shundo Y, Tjiri H, Tnk M, Ymshit N, Kohjim M, et l. Liver X receptor in coopertion with SREBP-1c is mjor lipid synthesis regultor in nonlcoholic ftty liver disese. Heptol Res 2008; 38: Kleiner DE, Brunt EM, Vn Ntt M, Behling C, Contos MJ, Cummings OW, Ferrell LD, et l. Design nd vlidtion of histologicl scoring system for nonlcoholic ftty liver disese. Heptology 2005; 41:
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