The efficacy of fenofibrate in the treatment of hepatic steatosis has not been clearly demonstrated. In this study, we investigated the effects of fenofibrate and silymarin, administered as monotherapy and in combination to existing hepatic steatosis in a unique strain of hereditary hypertriglyceridemic rats (HHTg), a non-obese model of metabolic syndrome. HHTg rats were fed a standard diet without or with fenofibrate (100 mg/kg b.wt./day) or with silymarin (1%) or with a combination of fenofibrate with silymarin for four weeks. Fenofibrate alone and in combination with silymarin decreased serum and liver triglycerides and cholesterol and increased HDL cholesterol. These effects were associated with the decreased gene expression of enzymes involved in lipid synthesis and transport, while enzymes of lipid conversion were upregulated. The combination treatment had a beneficial effect on the gene expression of hepatic cytochrome P450 (CYP) enzymes. The expression of the CYP2E1 enzyme, which is source of hepatic reactive oxygen species, was reduced. In addition, fenofibrate-induced increased CYP4A1 expression was decreased, suggesting a reduction in the pro-inflammatory effects of fenofibrate. These results show high efficacy and mechanisms of action of the combination of fenofibrate with silymarin in treating hepatic steatosis and indicate the possibility of protection against disorders in which oxidative stress and inflammation are involved.

Centre for Experimental Medicine Institute for Clinical and Experimental Medicine 14021 Prague Czech Republic

Department of Pharmacology Faculty of Medicine and Dentistry Palacky University 77515 Olomouc Czech Republic

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Byrne C.D., Targher G. NAFLD: A Multisystem Disease. J. Hepatol. 2015;62:S47–S64. doi: 10.1016/j.jhep.2014.12.012. PubMed DOI

Smits M.M., Ioannou G.N., Boyko E.J., Utzschneider K.M. Non-Alcoholic Fatty Liver Disease as an Independent Manifestation of the Metabolic Syndrome: Results of a US National Survey in Three Ethnic Groups. J. Gastroenterol. Hepatol. 2013;28:664–670. doi: 10.1111/jgh.12106. PubMed DOI

Geisler C.E., Renquist B.J. Hepatic Lipid Accumulation: Cause and Consequence of Dysregulated Glucoregulatory Hormones. J. Endocrinol. 2017;234:R1–R21. doi: 10.1530/JOE-16-0513. PubMed DOI

Lefebvre P., Chinetti G., Fruchart J.C., Staels B. Sorting out the Roles of PPARα in Energy Metabolism and Vascular Homeostasis. J. Clin. Investig. 2006;116:571–580. doi: 10.1172/JCI27989. PubMed DOI PMC

McCullough P.A., Ahmed A.B., Zughaib M.T., Glanz E.D., di Loreto M.J. Treatment of Hypertriglyceridemia with Fibric Acid Derivatives: Impact on Lipid Subfractions and Translation into a Reduction in Cardiovascular Events. Rev. Cardiovasc. Med. 2011;12:173–185. doi: 10.3909/ricm0619. PubMed DOI

Bajaj M., Suraamornkul S., Hardies L.J., Glass L., Musi N., DeFronzo R.A. Effects of Peroxisome Proliferator-Activated Receptor (PPAR)-α and PPAR-γ Agonists on Glucose and Lipid Metabolism in Patients with Type 2 Diabetes Mellitus. Diabetologia. 2007;50:1723–1731. doi: 10.1007/s00125-007-0698-9. PubMed DOI

Fernández-Miranda C., Pérez-Carreras M., Colina F., López-Alonso G., Vargas C., Solís-Herruzo J.A. A Pilot Trial of Fenofibrate for the Treatment of Non-Alcoholic Fatty Liver Disease. Dig. Liver Dis. 2008;40:200–205. doi: 10.1016/j.dld.2007.10.002. PubMed DOI

Fabbrini E., Mohammed B.S., Korenblat K.M., Magkos F., McCrea J., Patterson B.W., Klein S. Effect of Fenofibrate and Niacin on Intrahepatic Triglyceride Content, Very Low-Density Lipoprotein Kinetics, and Insulin Action in Obese Subjects with Nonalcoholic Fatty Liver Disease. J. Clin. Endocrinol. Metab. 2010;95:2727–2735. doi: 10.1210/jc.2009-2622. PubMed DOI PMC

Oscarsson J., Önnerhag K., Risérus U., Sundén M., Johansson L., Jansson P.A., Moris L., Nilsson P.M., Eriksson J.W., Lind L. Effects of Free Omega-3 Carboxylic Acids and Fenofibrate on Liver Fat Content in Patients with Hypertriglyceridemia and Non-Alcoholic Fatty Liver Disease: A Double-Blind, Randomized, Placebo-Controlled Study. J. Clin. Lipidol. 2018;12:1390–1403. doi: 10.1016/j.jacl.2018.08.003. PubMed DOI

Tailleux A., Wouters K., Staels B. Roles of PPARs in NAFLD: Potential Therapeutic Targets. Biochim. Biophys. Acta. 2012;1821:809–818. doi: 10.1016/j.bbalip.2011.10.016. PubMed DOI

Waterman I.J., Zammit V.A. Differential Effects of Fenofibrate or Simvastatin Treatment of Rats on Hepatic Microsomal Overt and Latent Diacylglycerol Acyltransferase Activities. Diabetes. 2002;51:1708–1713. doi: 10.2337/diabetes.51.6.1708. PubMed DOI

Edvardsson U., Ljungberg A., Lindén D., William-Olsson L., Peilot-Sjögren H., Ahnmark A., Oscarsson J. PPARα Activation Increases Triglyceride Mass and Adipose Differentiation-Related Protein in Hepatocytes. J. Lipid Res. 2006;47:329–340. doi: 10.1194/jlr.M500203-JLR200. PubMed DOI

Yan F., Wang Q., Xu C., Cao M., Zhou X., Wang T., Yu C., Jing F., Chen W., Gao L., et al. Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect. PLoS ONE. 2014;9:e99245. doi: 10.1371/journal.pone.0099245. PubMed DOI PMC

Ahmad J., Odin J.A., Hayashi P.H., Chalasani N., Fontana R.J., Barnhart H., Cirulli E.T., Kleiner D.E., Hoofnagle J.H. Identification and Characterization of Fenofibrate-Induced Liver Injury. Dig. Dis. Sci. 2017;62:3596–3604. doi: 10.1007/s10620-017-4812-7. PubMed DOI PMC

Škop V., Trnovská J., Oliyarnyk O., Marková I., Malínská H., Kazdová L., Zídek V., Landa V., Mlejnek P., Šimáková M., et al. Hepatotoxic Effects of Fenofibrate in Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein. Physiol. Res. 2016;65:891–899. doi: 10.33549/physiolres.933304. PubMed DOI

Vargas-Mendoza N., Madrigal-Santillán E., Morales-González A., Esquivel-Soto J., Esquivel-Chirino C., García-Luna Y., González-Rubio M., Gayosso-de-Lucio J.A., Morales-González J.A. Hepatoprotective Effect of Silymarin. World J. Hepatol. 2014;6:144–149. doi: 10.4254/wjh.v6.i3.144. PubMed DOI PMC

Gillessen A., Schmidt H.H.J. Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review. Adv. Ther. 2020;37:1279–1301. doi: 10.1007/s12325-020-01251-y. PubMed DOI PMC

Škottová N., Kazdová L., Oliyarnyk O., Večeřa R., Sobolová L., Ulrichová J. Phenolics-Rich Extracts from Silybum Marianum and Prunella Vulgaris Reduce a High-Sucrose Diet Induced Oxidative Stress in Hereditary Hypertriglyceridemic Rats. Pharm. Res. 2004;50:123–130. doi: 10.1016/j.phrs.2003.12.013. PubMed DOI

Poruba M., Kazdová L., Oliyarnyk O., Malinská H., Matusková Z., Tozzi Di Angelo I., Skop V., Vecera R. Improvement Bioavailability of Silymarin Ameliorates Severe Dyslipidemia Associated with Metabolic Syndrome. Xenobiotica. 2015;45:751–756. doi: 10.3109/00498254.2015.1010633. PubMed DOI

Ebrahimpour-koujan S., Gargari B.P., Mobasseri M., Valizadeh H., Asghari-Jafarabadi M. Lower Glycemic Indices and Lipid Profile among Type 2 Diabetes Mellitus Patients Who Received Novel Dose of Silybum Marianum (L.) Gaertn. (Silymarin) Extract Supplement: A Triple-Blinded Randomized Controlled Clinical Trial. Phytomedicine. 2018;44:39–44. doi: 10.1016/j.phymed.2018.03.050. PubMed DOI

Mohammadi H., Hadi A., Arab A., Moradi S., Rouhani M.H. Effects of Silymarin Supplementation on Blood Lipids: A Systematic Review and Meta-Analysis of Clinical Trials. Phytother. Res. 2019;33:871–880. doi: 10.1002/ptr.6287. PubMed DOI

di Pierro F., Callegari A., Carotenuto D., Tapia M. Clinical Efficacy, Safety and Tolerability of BIO-C (Micronized Silymarin) as a Galactagogue. Acta Biomed. 2009;79:205–210. PubMed

Poruba M., Matušková Z., Kazdová L., Oliyarnyk O., Malínská H., Tozzi I., Angelo D.I., Večeřa R. Positive Effects of Different Drug Forms of Silybin in the Treatment of Metabolic Syndrome. Physiol. Res. 2015;64:507–512. doi: 10.33549/physiolres.933235. PubMed DOI

Vrána A., Kazdová L. The Hereditary Hypertriglyceridemic Nonobese Rat: An Experimental Model of Human Hypertriglyceridemia. Transpl. Proc. 1990;22:2579. PubMed

Zicha J., Pecháňová O., Čačányiová S., Cebová M., Kristek F., Török J., Šimko F., Dobešová Z., Kuneš J. Hereditary Hypertriglyceridemic Rat: A Suitable Model of Cardiovascular Disease and Metabolic Syndrome? Physiol. Res. 2006;55:49–63. PubMed

Škop V.C., Malínská H., Trnovská J., Hüttl M., Cahová M., Blachnio-Zabielska A., Baranowski M., Burian M., Oliyarnyk O., Kazdová L. Positive Effects of Voluntary Running on Metabolic Syndrome-Related Disorders in Non-Obese Hereditary Hypertriacylglycerolemic Rats. PLoS ONE. 2015;10:e0122768. doi: 10.1371/journal.pone.0122768. PubMed DOI PMC

Ye Q., Zou B., Yeo Y.H., Li J., Huang D.Q., Wu Y., Yang H., Liu C., Kam L.Y., Tan X.X.E., et al. Global Prevalence, Incidence, and Outcomes of Non-Obese or Lean Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Lancet Gastroenterol. Hepatol. 2020;5:739–752. doi: 10.1016/S2468-1253(20)30077-7. PubMed DOI

Ibarra-Lara L., Sánchez-Aguilar M., Sánchez-Mendoza A., del Valle-Mondragón L., Soria-Castro E., Carreón-Torres E., Díaz-Díaz E., Vázquez-Meza H., Guarner-Lans V., Rubio-Ruiz M.E. Fenofibrate Therapy Restores Antioxidant Protection and Improves Myocardial Insulin Resistance in a Rat Model of Metabolic Syndrome and Myocardial Ischemia: The Role of Angiotensin II. Molecules. 2016;22:31. doi: 10.3390/molecules22010031. PubMed DOI PMC

Goel S.K., Lalwani N.D., Reddy J.K. Peroxisome Proliferation and Lipid Peroxidation in Rat Liver. Cancer Res. 1986;46:1324–1330. PubMed

Poruba M., Matuskova Z., Hüttl M., Malinska H., Oliyarnyk O., Markova I., Gurska S., Kazdova L., Vecera R. Fenofibrate Decreases Hepatic P-Glycoprotein in a Rat Model of Hereditary Hypertriglyceridemia. Front. Pharm. 2019;10:56. doi: 10.3389/fphar.2019.00056. PubMed DOI PMC

Yu X.H., Zheng X.L., Tang C.K. Peroxisome Proliferator-Activated Receptor α in Lipid Metabolism and Atherosclerosis. Adv. Clin. Chem. 2015;71:171–203. PubMed

Montagner A., Polizzi A., Fouché E., Ducheix S., Lippi Y., Lasserre F., Barquissau V., Régnier M., Lukowicz C., Benhamed F., et al. Liver PPARα Is Crucial for Whole-Body Fatty Acid Homeostasis and Is Protective against NAFLD. Gut. 2016;65:1202–1214. doi: 10.1136/gutjnl-2015-310798. PubMed DOI PMC

Piccinin E., Cariello M., de Santis S., Ducheix S., Sabbà C., Ntambi J.M., Moschetta A. Role of Oleic Acid in the Gut-Liver Axis: From Diet to the Regulation of Its Synthesis via Stearoyl-CoA Desaturase 1 (SCD1) Nutrients. 2019;11:2283. doi: 10.3390/nu11102283. PubMed DOI PMC

Oosterveer M.H., Grefhorst A., van Dijk T.H., Havinga R., Staels B., Kuipers F., Groen A.K., Reijngoud D.J. Fenofibrate Simultaneously Induces Hepatic Fatty Acid Oxidation, Synthesis, and Elongation in Mice. J. Biol. Chem. 2009;284:34036–34044. doi: 10.1074/jbc.M109.051052. PubMed DOI PMC

Kersten S. Physiological Regulation of Lipoprotein Lipase. Biochim. Biophys. Acta. 2014;1841:919–933. doi: 10.1016/j.bbalip.2014.03.013. PubMed DOI

Jensen-Urstad A.P.L., Semenkovich C.F. Fatty Acid Synthase and Liver Triglyceride Metabolism: Housekeeper or Messenger? Biochim. Biophys. Acta. 2012;1821:747–753. doi: 10.1016/j.bbalip.2011.09.017. PubMed DOI PMC

Foucaud-Vignault M., Soayfane Z., Ménez C., Bertrand-Michel J., Martin P.G.P., Guillou H., Collet X., Lespine A. P-Glycoprotein Dysfunction Contributes to Hepatic Steatosis and Obesity in Mice. PLoS ONE. 2011;6:e23614. doi: 10.1371/journal.pone.0023614. PubMed DOI PMC

Ehrhardt M., Lindenmaier H., Burhenne J., Haefeli W.E., Weiss J. Influence of Lipid Lowering Fibrates on P-Glycoprotein Activity in Vitro. Biochem. Pharm. 2004;67:285–292. doi: 10.1016/j.bcp.2003.09.008. PubMed DOI

Russell D.W. The Enzymes, Regulation, and Genetics of Bile Acid Synthesis. Annu. Rev. Biochem. 2003;72:137–174. doi: 10.1146/annurev.biochem.72.121801.161712. PubMed DOI

Roglans N., Vázquez-Carrera M., Alegret M., Novell F., Zambón D., Ros E., Laguna J.C., Sánchez R.M. Fibrates Modify the Expression of Key Factors Involved in Bile-Acid Synthesis and Biliary-Lipid Secretion in Gallstone Patients. Eur. J. Clin. Pharm. 2003;59:855–861. PubMed

Shen J., Arnett D.K., Parnell L.D., Lai C.Q., Straka R.J., Hopkins P.N., An P., Feitosa M.F., Ordovás J.M. The Effect of CYP7A1 Polymorphisms on Lipid Responses to Fenofibrate. J. Cardiovasc. Pharm. 2012;59:254–259. doi: 10.1097/FJC.0b013e31823de86b. PubMed DOI PMC

Srivastava R.A.K., Cefalu A.B., Srivastava N.S., Averna M. NPC1L1 and ABCG5/8 Induction Explain Synergistic Fecal Cholesterol Excretion in Ob/Ob Mice Co-Treated with PPAR-α and LXR Agonists. Mol. Cell. Biochem. 2020;473:247–262. doi: 10.1007/s11010-020-03826-3. PubMed DOI

Ståhlberg D., Reihnér E., Ewerth S., Einarsson K., Angelin B. Effects of Bezafibrate on Hepatic Cholesterol Metabolism. Eur. J. Clin. Pharm. 1991;40:S33–S36. doi: 10.1007/BF03216286. PubMed DOI

Orolin J., Večeřa R., Jung D., Meyer U.A., Škottová N., Anzenbacher P. Hypolipidemic Effects of Silymarin Are Not Mediated by the Peroxisome Proliferator-Activated Receptor Alpha. Xenobiotica. 2008;37:725–735. doi: 10.1080/00498250701463333. PubMed DOI

Lupp A., Karge E., Deufel T., Oelschläger H., Fleck C. Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives: Effects of a Four-Week Treatment on Male Lean and Obese Zucker Rats. Arzneimittelforschung. 2008;58:225–241. PubMed

Federico A., Dallio M., Loguercio C. Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules. 2017;22:191. doi: 10.3390/molecules22020191. PubMed DOI PMC

Abenavoli L., Izzo A.A., Milić N., Cicala C., Santini A., Capasso R. Milk Thistle (Silybum Marianum): A Concise Overview on Its Chemistry, Pharmacological, and Nutraceutical Uses in Liver Diseases. Phytother. Res. 2018;32:2202–2213. doi: 10.1002/ptr.6171. PubMed DOI

Brites F., Martin M., Guillas I., Kontush A. Antioxidative Activity of High-Density Lipoprotein (HDL): Mechanistic Insights into Potential Clinical Benefit. BBA Clin. 2017;8:66–77. doi: 10.1016/j.bbacli.2017.07.002. PubMed DOI PMC

Xiao F., Gao F., Zhou S., Wang L. The Therapeutic Effects of Silymarin for Patients with Glucose/Lipid Metabolic Dysfunction: A Meta-Analysis. Medicine. 2020;99:e22249. doi: 10.1097/MD.0000000000022249. PubMed DOI PMC

Surai P.F. Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives. Antioxidants. 2015;4:204–247. doi: 10.3390/antiox4010204. PubMed DOI PMC

Ohta T., Masutomi N., Tsutsui N., Sakairi T., Mitchell M., Milburn M.V., Ryals J.A., Beebe K.D., Guo L. Untargeted Metabolomic Profiling as an Evaluative Tool of Fenofibrate-Induced Toxicology in Fischer 344 Male Rats. Toxicol. Pathol. 2009;37:521–535. doi: 10.1177/0192623309336152. PubMed DOI

Holeček M., Vodeničarovová M. Effects of Low and High Doses of Fenofibrate on Protein, Amino Acid, and Energy Metabolism in Rat. Int. J. Exp. Pathol. 2020;101:171–182. doi: 10.1111/iep.12368. PubMed DOI PMC

Johnson A.L., Edson K.Z., Totah R.A., Rettie A.E. Cytochrome P450 ω-Hydroxylases in Inflammation and Cancer. Adv. Pharm. 2015;74:223–262. PubMed PMC

Aubert J., Begriche K., Knockaert L., Robin M.A., Fromenty B. Increased Expression of Cytochrome P450 2E1 in Nonalcoholic Fatty Liver Disease: Mechanisms and Pathophysiological Role. Clin. Res. Hepatol. Gastroenterol. 2011;35:630–637. doi: 10.1016/j.clinre.2011.04.015. PubMed DOI

Leung T.M., Nieto N. CYP2E1 and Oxidant Stress in Alcoholic and Non-Alcoholic Fatty Liver Disease. J. Hepatol. 2013;58:395–398. doi: 10.1016/j.jhep.2012.08.018. PubMed DOI

Harjumäki R., Pridgeon C.S., Ingelman-Sundberg M. CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload. Int. J. Mol. Sci. 2021;22:8221. doi: 10.3390/ijms22158221. PubMed DOI PMC

Rolo A.P., Teodoro J.S., Palmeira C.M. Role of Oxidative Stress in the Pathogenesis of Nonalcoholic Steatohepatitis. Free Radic. Biol. Med. 2012;52:59–69. doi: 10.1016/j.freeradbiomed.2011.10.003. PubMed DOI