{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T23:34:57Z","timestamp":1767828897827,"version":"3.49.0"},"reference-count":41,"publisher":"Institute of Physiology of the Czech Academy of Sciences","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Physiol Res"],"published-print":{"date-parts":[[2015,12,28]]},"abstract":"<jats:p>The aim of the current study was to clarify the effect of high sucrose diet (HSD) on bile formation (BF) in rats with hereditary hypertriglyceridemia (HHTg). Potentially positive effects were studied for boldine, a natural choleretic agent. Administration of HSD to HHTg rats led to increased triglyceride deposition in the liver. HSD reduced BF as a consequence of decreased biliary secretion of bile acids (BA) and glutathione. Responsible mechanism was down-regulation of hepatic transporters for BA and glutathione, Bsep and Mrp2, respectively. Moreover, gene expressions of transporters for other constituents of bile, namely Abcg5\/8 for cholesterol, Abcb4 for phospholipids, and Oatp1a4 for xenobiotics, were also reduced by HSD. Boldine partially attenuated cholestatic effect of HSD by promotion of biliary secretion of BA through up-regulation of Bsep and Ntcp, and by increase in biliary secretion of glutathione as a consequence of its increased hepatic disposition. This study demonstrates mechanisms of impaired BF during nonalcoholic fatty liver disease induced by HSD. Altered function of responsible transporters suggests also potential for changes in kinetics of drugs, which may complicate pharmacotherapy in subjects with high intake of sucrose, and with fatty liver disease. Sucrose induced alterations in BF may be alleviated by administration of boldine.<\/jats:p>","DOI":"10.33549\/physiolres.933206","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T10:14:18Z","timestamp":1587636858000},"page":"S467-S476","source":"Crossref","is-referenced-by-count":16,"title":["Boldine Attenuates Cholestasis Associated With Nonalcoholic Fatty Liver Disease in Hereditary Hypertriglyceridemic Rats Fed by High-Sucrose Diet"],"prefix":"10.33549","author":[{"given":"M.","family":"ZAGOROVA","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"PRASNICKA","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Z.","family":"KADOVA","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"DOLEZELOVA","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"KAZDOVA","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"CERMANOVA","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"ROZKYDALOVA","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"HROCH","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"MOKRY","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"MICUDA","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"19169","published-online":{"date-parts":[[2015,12,12]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"ALI R, CUSI K: New diagnostic and treatment approaches in non-alcoholic fatty liver disease (NAFLD). Ann Med 41: 265-278, 2009.","DOI":"10.1080\/07853890802552437"},{"key":"ref1","doi-asserted-by":"publisher","unstructured":"BECHMANN LP, KOCABAYOGLU P, SOWA JP, SYDOR S, BEST J, SCHLATTJAN M, BEILFUSS A, SCHMITT J, HANNIVOORT RA, KILICARSLAN A, RUST C, BERR F, TSCHOPP O, GERKEN G, FRIEDMAN SL, GEIER A, CANBAY A: Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis. Hepatology 57: 1394-1406, 2013.","DOI":"10.1002\/hep.26225"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"BOYER JL: Bile formation and secretion. ComprPhysiol 3: 1035-1078, 2013.","DOI":"10.1002\/cphy.c120027"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"CANET MJ, HARDWICK RN, LAKE AD, DZIERLENGA AL, CLARKE JD, CHERRINGTON NJ: Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models. Drug Metab Dispos 42: 586-595, 2014.","DOI":"10.1124\/dmd.113.055996"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"CANET MJ, MERRELL MD, HARDWICK RN, BATAILLE AM, CAMPION SN, FERREIRA DW, XANTHAKOS SA, MANAUTOU JE, HESHAM AKH, ERICKSON RP, CHERRINGTON NJ: Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis. Drug Metab Dispos 43: 829-835, 2015.","DOI":"10.1124\/dmd.114.062703"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"CERMANOVA J, KADOVA Z, DOLEZELOVA-BRCAKOVA E, ZAGOROVA M, SAFKA V, HROCH M, LAHO T, HOLECKOVA M, MOKRY J, KOVARIKOVA P, BURES J, STERBA M, MICUDA S: Deferoxamine but not dexrazoxane alleviates liver injury induced by endotoxemia in rats. Shock 42: 372-379, 2014.","DOI":"10.1097\/shk.0000000000000210"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"CERMANOVA J, KADOVA Z, ZAGOROVA M, HROCH M, TOMSIK P, NACHTIGAL P, KUDLACKOVA Z, PAVEK P, DUBECKA M, CECKOVA M, STAUD F, LAHO T, MICUDA S: Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms. Toxicol Appl Pharmacol 285: 12-22, 2015.","DOI":"10.1016\/j.taap.2015.03.004"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"CHENG Q, ALEKSUNES LM, MANAUTOU JE, CHERRINGTON NJ, SCHEFFER GL, YAMASAKI H, SLITT AL: Drug-metabolizing enzyme and transporter expression in a mouse model of diabetes and obesity. Mol Pharmacol 5: 77-91, 2008.","DOI":"10.1021\/mp700114j"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"CUPERUS FJ, CLAUDEL T, GAUTHEROT J, HALILBASIC E, TRAUNER M: The role of canalicular ABC transporters in cholestasis. Drug Metab Dispos 42: 546-560, 2014.","DOI":"10.1124\/dmd.113.056358"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"DOWMAN JK, TOMLINSON JW, NEWSOME PN: Pathogenesis of non-alcoholic fatty liver disease. QJM 103: 71-83, 2010.","DOI":"10.1093\/qjmed\/hcp158"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"FERNANDEZ J, LAGOS P, RIVERA P, ZAMORANO-PONCE E: Effect of boldo (Peumus boldus Molina) infusion on lipoperoxidation induced by cisplatin in mice liver. Phytother Res 23: 1024-1027, 2009.","DOI":"10.1002\/ptr.2746"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"FERSLEW BC, JOHNSTON CK, TSAKALOZOU E, BRIDGES AS, PAINE MF, JIA W, STEWART PW, BARRITT AST, BROUWER KL: Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis. Clin Pharmacol Ther 97: 419-427, 2015.","DOI":"10.1002\/cpt.66"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"FIGGE A, LAMMERT F, PAIGEN B, HENKEL A, MATERN S, KORSTANJE R, SHNEIDER BL, CHEN F, STOLTENBERG E, SPATZ K, HODA F, COHEN DE, GREEN RM: Hepatic overexpression of murine Abcb11 increases hepatobiliary lipid secretion and reduces hepatic steatosis. J Biol Chem 279: 2790-2799, 2004.","DOI":"10.1074\/jbc.m307363200"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"FISHER CD, LICKTEIG AJ, AUGUSTINE LM, OUDE ELFERINK RP, BESSELSEN DG, ERICKSON RP, CHERRINGTON NJ: Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats. Eur J Pharmacol 613: 119-127, 2009.","DOI":"10.1016\/j.ejphar.2009.04.002"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"GEIER A, DIETRICH CG, GROTE T, BEUERS U, PRUFER T, FRAUNBERGER P, MATERN S, GARTUNG C, GERBES AL, BILZER M: Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat. J Hepatol 43: 1021-1030, 2005.","DOI":"10.1016\/j.jhep.2005.05.031"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"HALILBASIC E, CLAUDEL T, TRAUNER M: Bile acid transporters and regulatory nuclear receptors in the liver and beyond. J Hepatol 58: 155-168, 2013.","DOI":"10.1016\/j.jhep.2012.08.002"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"HARDWICK RN, FISHER CD, CANET MJ, SCHEFFER GL, CHERRINGTON NJ: Variations in ATP-binding cassette transporter regulation during the progression of human nonalcoholic fatty liver disease. Drug Metab Dispos 39: 2395-2402, 2011.","DOI":"10.1124\/dmd.111.041012"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"HIRSOVA P, KOLOUCHOVA G, DOLEZELOVA E, CERMANOVA J, HYSPLER R, KADOVA Z, MICUDA S: Epigallocatechin gallate enhances biliary cholesterol secretion in healthy rats and lowers plasma and liver cholesterol in ethinylestradiol-treated rats. Eur J Pharmacol 691: 38-45, 2012.","DOI":"10.1016\/j.ejphar.2012.06.034"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"HIRSOVA P, KARLASOVA G, DOLEZELOVA E, CERMANOVA J, ZAGOROVA M, KADOVA Z, HROCH M, SISPERA L, TOMSIK P, LENICEK M, VITEK L, PAVEK P, KUCERA O, CERVINKOVA Z, MICUDA S: Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2. Toxicology 303: 9-15, 2013.","DOI":"10.1016\/j.tox.2012.10.018"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"KLIMES I, VRANA A, KUNES J, SEBOKOVA E, DOBESOVA Z, STOLBA P, ZICHA J: Hereditary hypertriglyceridemic rat: a new animal model of metabolic alterations in hypertension. Blood Press 4: 137-142, 1995.","DOI":"10.3109\/08037059509077585"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"KOLOUCHOVA G, BRCAKOVA E, HIRSOVA P, CERMANOVA J, FUKSA L, MOKRY J, NACHTIGAL P, LASTUVKOVA H, MICUDA S: Modification of hepatic iron metabolism induced by pravastatin during obstructive cholestasis in rats. Life Sci 89: 717-724, 2011.","DOI":"10.1016\/j.lfs.2011.08.014"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"KONG B, CSANAKY IL, ALEKSUNES LM, PATNI M, CHEN Q, MA X, JAESCHKE H, WEIR S, BROWARD M, KLAASSEN CD, GUO GL: Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity. Toxicol Appl Pharmacol 261: 189-195, 2012.","DOI":"10.1016\/j.taap.2012.04.001"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"KUCERA O, ENDLICHER R, ROUSAR T, LOTKOVA H, GARNOL T, DRAHOTA Z, CERVINKOVA Z: The effect of tert-butyl hydroperoxide-induced oxidative stress on lean and steatotic rat hepatocytes in vitro. Oxid Med Cell Longev 2014: 752506, 2014.","DOI":"10.1155\/2014\/752506"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"LANHERS MC, JOYEUX M, SOULIMANI R, FLEURENTIN J, SAYAG M, MORTIER F, YOUNOS C, PELT JM: Hepatoprotective and anti-inflammatory effects of a traditional medicinal plant of Chile, Peumus boldus. Planta Med 57: 110-115, 1991.","DOI":"10.1055\/s-2006-960043"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"LAU YS, TIAN XY, HUANG Y, MURUGAN D, ACHIKE FI, MUSTAFA MR: Boldine protects endothelial function in hyperglycemia-induced oxidative stress through an antioxidant mechanism. Biochem Pharmacol 85: 367-375, 2013.","DOI":"10.1016\/j.bcp.2012.11.010"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"LICKTEIG AJ, FISHER CD, AUGUSTINE LM, ALEKSUNES LM, BESSELSEN DG, SLITT AL, MANAUTOU JE, CHERRINGTON NJ: Efflux transporter expression and acetaminophen metabolite excretion are altered in rodent models of nonalcoholic fatty liver disease. Drug Metab Dispos 35: 1970-1978, 2007.","DOI":"10.1124\/dmd.107.015107"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"MORE VR, SLITT AL: Alteration of hepatic but not renal transporter expression in diet-induced obese mice. Drug Metab Dispos 39: 992-999, 2011.","DOI":"10.1124\/dmd.110.037507"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"PIZARRO M, BALASUBRAMANIYAN N, SOLIS N, SOLAR A, DUARTE I, MIQUEL JF, SUCHY FJ, TRAUNER M, ACCATINO L, ANANTHANARAYANAN M, ARRESE M: Bile secretory function in the obese Zucker rat: evidence of cholestasis and altered canalicular transport function. Gut 53: 1837-1843, 2004.","DOI":"10.1136\/gut.2003.037689"},{"key":"ref28","doi-asserted-by":"publisher","unstructured":"SAAB KR, KENDRICK J, YRACHETA JM, LANASPA MA, POLLARD M, JOHNSON RJ: New insights on the risk for cardiovascular disease in African Americans: the role of added sugars. J Am Soc Nephrol 26: 247-257, 2015.","DOI":"10.1681\/asn.2014040393"},{"key":"ref29","doi-asserted-by":"publisher","unstructured":"SANYAL AJ: Use of farnesoid X receptor agonists to treat nonalcoholic fatty liver disease. Digestive diseases 33: 426-432, 2015.","DOI":"10.1159\/000371698"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"SCHMITT J, KONG B, STIEGER B, TSCHOPP O, SCHULTZE SM, RAU M, WEBER A, MULLHAUPT B, GUO GL, GEIER A: Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal. Liver Int 35: 1133-1144, 2015.","DOI":"10.1111\/liv.12456"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"SCHRIEBER SJ, WEN Z, VOURVAHIS M, SMITH PC, FRIED MW, KASHUBA AD, HAWKE RL: The pharmacokinetics of silymarin is altered in patients with hepatitis C virus and nonalcoholic fatty liver disease and correlates with plasma caspase-3\/7 activity. Drug Metab Dispos 36: 1909-1916, 2008.","DOI":"10.1124\/dmd.107.019604"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"SKOTTOVA N, KAZDOVA L, OLIYARNYK O, VECERA R, SOBOLOVA L, ULRICHOVA J: Phenolics-rich extracts from Silybum marianum and Prunella vulgaris reduce a high-sucrose diet induced oxidative stress in hereditary hypertriglyceridemic rats. Pharmacol Res 50: 123-130, 2004.","DOI":"10.1016\/j.phrs.2003.12.013"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"SORRENTINO P, TARANTINO G, PERRELLA A, MICHELI P, PERRELLA O, CONCA P: A clinical-morphological study on cholestatic presentation of nonalcoholic fatty liver disease. Dig Dis Sci 50: 1130-1135, 2005.","DOI":"10.1007\/s10620-005-2719-1"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"SUNDARAM SS, WHITINGTON PF, GREEN RM: Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a methionine-choline-deficient diet. Am J Physiol Gastrointest Liver Physiol 288: G1321-G1327, 2005.","DOI":"10.1152\/ajpgi.00455.2004"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"TAKAHASHI Y, FUKUSATO T: Histopathology of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis. World J Gastroenterol 20: 15539-15548, 2014.","DOI":"10.3748\/wjg.v20.i42.15539"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"THOMAS C, PELLICCIARI R, PRUZANSKI M, AUWERX J, SCHOONJANS K: Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov 7: 678-693, 2008.","DOI":"10.1038\/nrd2619"},{"key":"ref37","unstructured":"VRANA A, KAZDOVA L: The hereditary hypertriglyceridemic nonobese rat: an experimental model of human hypertriglyceridemia. Transplant Proc 22: 2579, 1990."},{"key":"ref38","doi-asserted-by":"publisher","unstructured":"VRANA A, KAZDOVA L, DOBESOVA Z, KUNES J, KREN V, BILA V, STOLBA P, KLIMES I: Triglyceridemia, glucoregulation, and blood pressure in various rat strains. Effects of dietary carbohydrates. Ann N Y Acad Sci 683: 57-68, 1993.","DOI":"10.1111\/j.1749-6632.1993.tb35692.x"},{"key":"ref39","doi-asserted-by":"publisher","unstructured":"WU WB, CHEN YY, ZHU B, PENG XM, ZHANG SW, ZHOU ML: Excessive bile acid activated NF-kappa B and promoted the development of alcoholic steatohepatitis in farnesoid X receptor deficient mice. Biochimie 115: 86-92, 2015.","DOI":"10.1016\/j.biochi.2015.05.014"},{"key":"ref40","doi-asserted-by":"publisher","unstructured":"ZHANG S, WANG J, LIU Q, HARNISH DC: Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 51: 380-388, 2009.","DOI":"10.1016\/j.jhep.2009.03.025"}],"container-title":["Physiological Research"],"original-title":[],"language":"en","deposited":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T10:14:23Z","timestamp":1587636863000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.biomed.cas.cz\/physiolres\/pdf\/64%20Suppl%204\/64_S467.pdf"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,12]]},"references-count":41,"URL":"https:\/\/doi.org\/10.33549\/physiolres.933206","relation":{},"ISSN":["1802-9973","0862-8408"],"issn-type":[{"value":"1802-9973","type":"electronic"},{"value":"0862-8408","type":"print"}],"subject":[],"published":{"date-parts":[[2015,12,12]]}}}