Generic placeholder image

The International Journal of Gastroenterology and Hepatology Diseases

Editor-in-Chief

ISSN (Print): 2666-2906
ISSN (Online): 2666-2914

Research Article

Deoxycholic and Ursodeoxycholic Acid Differentially Impact Cellular Steatosis and Lipid Peroxidation in Cultured Hepatoma Cells

Author(s): Laura Vergani, Francesca Baldini, Mohamad Khalil, Nadia Serale, Jacek Baj, Agostino Di Ciaula and Piero Portincasa*

Volume 1, Issue 1, 2022

Published on: 26 November, 2021

Article ID: e210421192957 Pages: 10

DOI: 10.2174/2666290601666210421132727

Open Access Journals Promotions 2
Abstract

Background: Bile acids (BAs) are the major lipid components of bile. They are synthesized from cholesterol in the liver and stored in the gallbladder. BAs have gained attention as drug candidates to control obesity and/or diabetic condition due to their role in lipid and glucose metabolism.

Objective: This study aimed to evaluate the antisteatotic and antioxidant potential of deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), two BAs with opposite physico-chemical features.

Methods: Different concentrations of DCA and UDCA in the micromolar range were tested on cultured hepatoma cells after loading with an excess of fatty acids to mimic non-alcoholic fatty liver disease (NAFLD) in vitro. Experimental analyses included cell viability, lipid accumulation and lipid peroxidation in steatotic hepatocytes before and after exposure to either DCA or UDCA.

Results: Both UDCA and DCA improved lipid dysmetabolism and oxidative stress conditions in the steatotic hepatocytes. However, while UDCA was more effective as lipid lowering agent, DCA showed a greater antioxidant effect.

Conclusion: UDCA seems to have better protective and beneficial potential than DCA, as it is able to both alleviate lipid accumulation in the steatotic liver cells, but also to play antioxidant effect.

Keywords: Bile acids, hepatic steatosis, non-alcoholic fatty liver disease, oxidative stress, antioxidant effect, lipid dysmetabolism.

Graphical Abstract
[1]
Di Ciaula, A.; Garruti, G.; Lunardi Baccetto, R.; Molina-Molina, E.; Bonfrate, L.; Wang, D. Q. Portincasa, p. bile acid physiology. Ann. Hepato, 2017, 16(Suppl. 1: s3-105), s4-s14.
[http://dx.doi.org/10.5604/01.3001.0010.5493]
[2]
Di Ciaula, A.; Wang, D. Q.; Molina-Molina, E.; Lunardi Baccetto, R.; Calamita, G.; Palmieri, V. O. Portincasa, p. bile acids and cancer: direct and environmental-dependent effects. Ann. hepatol., 2017, 16(Suppl. 1: s3-105), s87-s105.
[3]
Garruti, G.; Di Ciaula, A.; Wang, H. H.; Wang, D. Q. Portincasa, p. cross-talk between bile acids and gastro-intestinal and thermogenic hormones: clues from bariatric surgery. Annals of hepato., 2017, 16(Suppl. 1: s3-105), s68-s82.
[4]
Ahmad, T.R.; Haeusler, R.A. Bile acids in glucose metabolism and insulin signalling - mechanisms and research needs. Nat. Rev. Endocrinol., 2019, 15(12), 701-712.
[http://dx.doi.org/10.1038/s41574-019-0266-7] [PMID: 31616073]
[5]
Perez, M.J.; Briz, O. Bile-acid-induced cell injury and protection. World J. Gastroenterol., 2009, 15(14), 1677-1689.
[http://dx.doi.org/10.3748/wjg.15.1677] [PMID: 19360911]
[6]
Cao, H.; Xu, M.; Dong, W.; Deng, B.; Wang, S.; Zhang, Y.; Wang, S.; Luo, S.; Wang, W.; Qi, Y.; Gao, J.; Cao, X.; Yan, F.; Wang, B. Secondary bile acid-induced dysbiosis promotes intestinal carcinogenesis. Int. J. Cancer, 2017, 140(11), 2545-2556.
[http://dx.doi.org/10.1002/ijc.30643] [PMID: 28187526]
[7]
Othman, M.O.; Dunkelberg, J.; Roy, P.K. Urosdeoxycholic acid in primary sclerosing cholangitis: a meta-analysis and systematic review. Arab J. Gastroenterol., 2012, 13(3), 103-110.
[http://dx.doi.org/10.1016/j.ajg.2012.06.011] [PMID: 23122450]
[8]
Ascher, B.; Fellmann, J.; Monheit, G. ATX-101 (deoxycholic acid injection) for reduction of submental fat. Expert Rev. Clin. Pharmacol., 2016, 9(9), 1131-1143.
[http://dx.doi.org/10.1080/17512433.2016.1215911] [PMID: 27457304]
[9]
Portincasa, P.; Wang, D.Q.H. Gallstones. In: Yamada's Atlas of Gastroenterology, 5th ed.; Podolsky, K. D.; Camilleri, M.; Fitz, J. G.; Kalloo, A. N.; Shanahan, F.; Wang, T. C. Wiley-Blackwell: Hoboken, New Jersey (USA), 2016, pp. 335-353.
[10]
Poupon, R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin. Res. Hepatol. Gastroenterol., 2012, 36(Suppl. 1), S3-S12.
[http://dx.doi.org/10.1016/S2210-7401(12)70015-3] [PMID: 23141891]
[11]
Mahmoud, A.A.; Elshazly, S.M. Ursodeoxycholic acid ameliorates fructose-induced metabolic syndrome in rats. PLoS One, 2014, 9(9), e106993.
[http://dx.doi.org/10.1371/journal.pone.0106993] [PMID: 25202970]
[12]
Oh, A.R.; Bae, J.S.; Lee, J.; Shin, E.; Oh, B.C.; Park, S.C.; Cha, J.Y. Ursodeoxycholic acid decreases age-related adiposity and inflammation in mice. BMB Rep., 2016, 49(2), 105-110.
[http://dx.doi.org/10.5483/BMBRep.2016.49.2.173] [PMID: 26350747]
[13]
Quintero, P.; Pizarro, M.; Solís, N.; Arab, J.P.; Padilla, O.; Riquelme, A.; Arrese, M. Bile acid supplementation improves established liver steatosis in obese mice independently of glucagon-like peptide-1 secretion. J. Physiol. Biochem., 2014, 70(3), 667-674.
[http://dx.doi.org/10.1007/s13105-014-0336-1] [PMID: 24816727]
[14]
Mueller, M.; Thorell, A.; Claudel, T.; Jha, P.; Koefeler, H.; Lackner, C.; Hoesel, B.; Fauler, G.; Stojakovic, T.; Einarsson, C.; Marschall, H.U.; Trauner, M. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity. J. Hepatol., 2015, 62(6), 1398-1404.
[http://dx.doi.org/10.1016/j.jhep.2014.12.034] [PMID: 25617503]
[15]
Baldini, F.; Bartolozzi, A.; Ardito, M.; Voci, A.; Portincasa, P.; Vassalli, M.; Vergani, L. Biomechanics of cultured hepatic cells during different steatogenic hits. J. Mech. Behav. Biomed. Mater., 2019, 97, 296-305.
[http://dx.doi.org/10.1016/j.jmbbm.2019.05.036] [PMID: 31151002]
[16]
Eckel, R.H.; Alberti, K.G.; Grundy, S.M.; Zimmet, P.Z. The metabolic syndrome. Lancet, 2010, 375(9710), 181-183.
[http://dx.doi.org/10.1016/S0140-6736(09)61794-3] [PMID: 20109902]
[17]
Vecchione, G.; Grasselli, E.; Cioffi, F.; Baldini, F.; Oliveira, P.J.; Sardão, V.A.; Cortese, K.; Lanni, A.; Voci, A.; Portincasa, P.; Vergani, L. The nutraceutic silybin counteracts excess lipid accumulation and ongoing oxidative stress in an in vitro model of non-alcoholic fatty liver disease progression. Front. Nutr., 2017, 4, 42.
[http://dx.doi.org/10.3389/fnut.2017.00042] [PMID: 28971098]
[18]
Molina-Molina, E.; Lunardi Baccetto, R.; Wang, D.Q.; de Bari, O.; Krawczyk, M.; Portincasa, P. Exercising the hepatobiliary-gut axis. The impact of physical activity performance. Eur. J. Clin. Invest., 2018, 48(8), e12958.
[http://dx.doi.org/10.1111/eci.12958] [PMID: 29797516]
[19]
Dufour, J.F.; Caussy, C.; Loomba, R. Combination therapy for non-alcoholic steatohepatitis: rationale, opportunities and challenges. Gut, 2020, 69(10), 1877-1884.
[http://dx.doi.org/10.1136/gutjnl-2019-319104] [PMID: 32381514]
[20]
Grasselli, E.; Baldini, F.; Vecchione, G.; Oliveira, P.J.; Sardão, V.A.; Voci, A.; Portincasa, P.; Vergani, L. Excess fructose and fatty acids trigger a model of non alcoholic fatty liver disease progression in vitro: Protective effect of the flavonoid silybin. Int. J. Mol. Med., 2019, 44(2), 705-712.
[http://dx.doi.org/10.3892/ijmm.2019.4234] [PMID: 31173180]
[21]
Clayton, D.F.; Weiss, M.; Darnell, J.E. Jr Liver-specific RNA metabolism in hepatoma cells: variations in transcription rates and mRNA levels. Mol. Cell. Biol., 1985, 5(10), 2633-2641.
[http://dx.doi.org/10.1128/MCB.5.10.2633] [PMID: 3841793]
[22]
Joshi-Barve, S.; Barve, S.S.; Amancherla, K.; Gobejishvili, L.; Hill, D.; Cave, M.; Hote, P.; McClain, C.J. Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes. Hepatology, 2007, 46(3), 823-830.
[http://dx.doi.org/10.1002/hep.21752] [PMID: 17680645]
[23]
Grasselli, E.; Canesi, L.; Portincasa, P.; Voci, A.; Vergani, L.; Demori, I. Models of non-alcoholic fatty liver disease and potential translational value: the effects of 3,5-L-diiodothyronine. Ann. Hepatol., 2017, 16(5), 707-719.
[http://dx.doi.org/10.5604/01.3001.0010.2713] [PMID: 28809727]
[24]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72, 248-254.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[25]
Vergani, L.; Vecchione, G.; Baldini, F.; Grasselli, E.; Voci, A.; Portincasa, P.; Ferrari, P.F.; Aliakbarian, B.; Casazza, A.A.; Perego, P. Polyphenolic extract attenuates fatty acid-induced steatosis and oxidative stress in hepatic and endothelial cells. Eur. J. Nutr., 2018, 57(5), 1793-1805.
[http://dx.doi.org/10.1007/s00394-017-1464-5] [PMID: 28526925]
[26]
Grasselli, E.; Voci, A.; Canesi, L.; De Matteis, R.; Goglia, F.; Cioffi, F.; Fugassa, E.; Gallo, G.; Vergani, L. Direct effects of iodothyronines on excess fat storage in rat hepatocytes. J. Hepatol., 2011, 54(6), 1230-1236.
[http://dx.doi.org/10.1016/j.jhep.2010.09.027] [PMID: 21145833]
[27]
Iguchi, H.; Kojo, S.; Ikeda, M. Lipid peroxidation and disintegration of the cell membrane structure in cultures of rat lung fibroblasts treated with asbestos. J. Appl. Toxicol., 1993, 13(4), 269-275.
[http://dx.doi.org/10.1002/jat.2550130409] [PMID: 8376727]
[28]
Bomzon, A.; Ljubuncic, P. Ursodeoxycholic acid and in vitro vasoactivity of hydrophobic bile acids. Dig. Dis. Sci., 2001, 46(9), 2017-2024.
[http://dx.doi.org/10.1023/A:1010663904820] [PMID: 11575458]
[29]
Ljubuncic, P.; Fuhrman, B.; Oiknine, J.; Aviram, M.; Bomzon, A. Effect of deoxycholic acid and ursodeoxycholic acid on lipid peroxidation in cultured macrophages. Gut, 1996, 39(3), 475-478.
[http://dx.doi.org/10.1136/gut.39.3.475] [PMID: 8949657]
[30]
Im, E.; Martinez, J.D. Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/Raf-1/ERK signaling in human colon cancer cells. J. Nutr., 2004, 134(2), 483-486.
[http://dx.doi.org/10.1093/jn/134.2.483] [PMID: 14747693]
[31]
Moustafa, T.; Fickert, P.; Magnes, C.; Guelly, C.; Thueringer, A.; Frank, S.; Kratky, D.; Sattler, W.; Reicher, H.; Sinner, F.; Gumhold, J.; Silbert, D.; Fauler, G.; Höfler, G.; Lass, A.; Zechner, R.; Trauner, M. Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology, 2012, 142(1), 140-151.e12.
[http://dx.doi.org/10.1053/j.gastro.2011.09.051] [PMID: 22001865]
[32]
Di Ciaula, A.; Wang, D.Q.; Portincasa, P. An update on the pathogenesis of cholesterol gallstone disease. Curr. Opin. Gastroenterol., 2018, 34(2), 71-80.
[http://dx.doi.org/10.1097/MOG.0000000000000423] [PMID: 29283909]
[33]
Poupon, R.E.; Lindor, K.D.; Cauch-Dudek, K.; Dickson, E.R.; Poupon, R.; Heathcote, E.J. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology, 1997, 113(3), 884-890.
[http://dx.doi.org/10.1016/S0016-5085(97)70183-5] [PMID: 9287980]
[34]
Bacq, Y.; Sentilhes, L.; Reyes, H.B.; Glantz, A.; Kondrackiene, J.; Binder, T.; Nicastri, P.L.; Locatelli, A.; Floreani, A.; Hernandez, I.; Di Martino, V. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology, 2012, 143(6), 1492-1501.
[http://dx.doi.org/10.1053/j.gastro.2012.08.004] [PMID: 22892336]
[35]
Goossens, J.F.; Bailly, C. Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy. Pharmacol. Ther., 2019, 203, 107396.
[http://dx.doi.org/10.1016/j.pharmthera.2019.107396] [PMID: 31356908]
[36]
Gheibi, S.; Gouvarchin Ghaleh, H.E.; Motlagh, B.M.; Azarbayjani, A.F.; Zarei, L. Therapeutic effects of curcumin and ursodexycholic acid on non-alcoholic fatty liver disease. Biomed. Pharmacother., 2019, 115, 108938.
[http://dx.doi.org/10.1016/j.biopha.2019.108938] [PMID: 31071511]
[37]
Lindor, K.D.; Kowdley, K.V.; Heathcote, E.J.; Harrison, M.E.; Jorgensen, R.; Angulo, P.; Lymp, J.F.; Burgart, L.; Colin, P. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology, 2004, 39(3), 770-778.
[http://dx.doi.org/10.1002/hep.20092] [PMID: 14999696]
[38]
Chiang, J.Y.L.; Ferrell, J.M. Bile Acid metabolism in liver pathobiology. Gene Expr., 2018, 18(2), 71-87.
[http://dx.doi.org/10.3727/105221618X15156018385515] [PMID: 29325602]
[39]
Martinez-Diez, M.C.; Serrano, M.A.; Monte, M.J.; Marin, J.J. Comparison of the effects of bile acids on cell viability and DNA synthesis by rat hepatocytes in primary culture. Biochim. Biophys. Acta, 2000, 1500(2), 153-160.
[http://dx.doi.org/10.1016/S0925-4439(99)00099-X] [PMID: 10657584]
[40]
Zou, B.; Yeo, Y.H.; Nguyen, V.H.; Cheung, R.; Ingelsson, E.; Nguyen, M.H. Prevalence, characteristics and mortality outcomes of obese, nonobese and lean NAFLD in the United States, 1999-2016. J. Intern. Med., 2020, 288(1), 139-151.
[http://dx.doi.org/10.1111/joim.13069] [PMID: 32319718]
[41]
Angelin, B.; Hershon, K.S.; Brunzell, J.D. Bile acid metabolism in hereditary forms of hypertriglyceridemia: evidence for an increased synthesis rate in monogenic familial hypertriglyceridemia. Proc. Natl. Acad. Sci. USA, 1987, 84(15), 5434-5438.
[http://dx.doi.org/10.1073/pnas.84.15.5434] [PMID: 3474660]
[42]
Petrosillo, G.; Portincasa, P.; Grattagliano, I.; Casanova, G.; Matera, M.; Ruggiero, F.M.; Ferri, D.; Paradies, G. Mitochondrial dysfunction in rat with nonalcoholic fatty liver Involvement of complex I, reactive oxygen species and cardiolipin. Biochim. Biophys. Acta, 2007, 1767(10), 1260-1267.
[http://dx.doi.org/10.1016/j.bbabio.2007.07.011] [PMID: 17900521]
[43]
Thomas, C.; Pellicciari, R.; Pruzanski, M.; Auwerx, J.; Schoonjans, K. Targeting bile-acid signalling for metabolic diseases. Nat. Rev. Drug Discov., 2008, 7(8), 678-693.
[http://dx.doi.org/10.1038/nrd2619] [PMID: 18670431]
[44]
Zhu, Y.; Liu, H.; Zhang, M.; Guo, G.L. Fatty liver diseases, bile acids, and FXR. Acta Pharm. Sin. B, 2016, 6(5), 409-412.
[http://dx.doi.org/10.1016/j.apsb.2016.07.008] [PMID: 27709009]
[45]
Li, Y.; Jadhav, K.; Zhang, Y. Bile acid receptors in non-alcoholic fatty liver disease. Biochem. Pharmacol., 2013, 86(11), 1517-1524.
[http://dx.doi.org/10.1016/j.bcp.2013.08.015] [PMID: 23988487]
[46]
Sousa, T.; Castro, R.E.; Pinto, S.N.; Coutinho, A.; Lucas, S.D.; Moreira, R.; Rodrigues, C.M.; Prieto, M.; Fernandes, F. Deoxycholic acid modulates cell death signaling through changes in mitochondrial membrane properties. J. Lipid Res., 2015, 56(11), 2158-2171.
[http://dx.doi.org/10.1194/jlr.M062653] [PMID: 26351365]
[47]
Chen, Y.S.; Liu, H.M.; Lee, T.Y. Ursodeoxycholic acid regulates hepatic energy homeostasis and white adipose tissue macrophages polarization in leptin-deficiency obese mice. Cells, 2019, 8(3), E253.
[http://dx.doi.org/10.3390/cells8030253] [PMID: 30884843]
[48]
Traussnigg, S.; Schattenberg, J.M.; Demir, M.; Wiegand, J.; Geier, A.; Teuber, G.; Hofmann, W.P.; Kremer, A.E.; Spreda, F.; Kluwe, J.; Petersen, J.; Boettler, T.; Rainer, F.; Halilbasic, E.; Greinwald, R.; Pröls, M.; Manns, M.P.; Fickert, P.; Trauner, M. Austrian/German NAFLD-norUDCA study group. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol. Hepatol., 2019, 4(10), 781-793.
[http://dx.doi.org/10.1016/S2468-1253(19)30184-0] [PMID: 31345778]
[49]
Calkin, A.C.; Tontonoz, P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat. Rev. Mol. Cell Biol., 2012, 13(4), 213-224.
[http://dx.doi.org/10.1038/nrm3312] [PMID: 22414897]
[50]
de Aguiar Vallim, T.Q.; Tarling, E.J.; Edwards, P.A. Pleiotropic roles of bile acids in metabolism. Cell Metab., 2013, 17(5), 657-669.
[http://dx.doi.org/10.1016/j.cmet.2013.03.013] [PMID: 23602448]
[51]
Safadi, R.; Konikoff, F. M.; Mahamid, M.; Zelber-Sagi, S.; Halpern, M.; Gilat, T.; Oren, R. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2014, 12(12), 2085-2091.e1.
[52]
Pockros, P.J.; Fuchs, M.; Freilich, B.; Schiff, E.; Kohli, A.; Lawitz, E.J.; Hellstern, P.A.; Owens-Grillo, J.; Van Biene, C.; Shringarpure, R.; MacConell, L.; Shapiro, D.; Cohen, D.E. CONTROL: A randomized phase 2 study of obeticholic acid and atorvastatin on lipoproteins in nonalcoholic steatohepatitis patients. Liver Int., 2019, 39(11), 2082-2093.
[http://dx.doi.org/10.1111/liv.14209] [PMID: 31402538]

© 2024 Bentham Science Publishers | Privacy Policy