{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T06:41:04Z","timestamp":1778740864449,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T00:00:00Z","timestamp":1574121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004191","name":"Novo Nordisk","doi-asserted-by":"publisher","award":["#1001110782"],"award-info":[{"award-number":["#1001110782"]}],"id":[{"id":"10.13039\/501100004191","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lifepharm centre for in vivo pharmacology","award":["#1001109652"],"award-info":[{"award-number":["#1001109652"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Despite affecting millions of patients worldwide, no pharmacological treatment has yet proved effective against non-alcoholic steatohepatitis (NASH) induced liver fibrosis. Current guidelines recommend lifestyle modifications including reductions in dietary energy intake. Recently, therapy with atorvastatin and vitamin E (vitE) has been recommended, although clinical studies on the resolution of hepatic fibrosis are inconclusive. Targeting NASH-induced hepatic end-points, this study evaluated the effects of atorvastatin and vitE alone or in combination with a dietary intervention in the guinea pig NASH model. Guinea pigs (n = 72) received 20 weeks of high fat feeding before allocating to four groups: continued HF feeding (HF), HF diet with atorvastatin and vitE (HF+), low-fat diet (LF) and low-fat with atorvastatin and vitE (LF+), for four or eight weeks of intervention. Both LF and LF+ decreased liver weight, cholesterol and plasma dyslipidemia. LF+ further improved hepatic histopathological hallmarks (p &lt; 0.05), liver injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (p &lt; 0.05) and reduced the expression of target genes of hepatic inflammation and fibrosis (p &lt; 0.05), underlining an increased effect on NASH resolution in this group. Collectively, the data support an overall beneficial effect of diet change, and indicate that atorvastatin and vitE therapy combined with a diet change act synergistically in improving NASH-induced endpoints.<\/jats:p>","DOI":"10.3390\/nu11112834","type":"journal-article","created":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T11:30:17Z","timestamp":1574163017000},"page":"2834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Atorvastatin and Vitamin E Accelerates NASH Resolution by Dietary Intervention in a Preclinical Guinea Pig Model"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8832-5106","authenticated-orcid":false,"given":"Julie Hviid","family":"Klaebel","sequence":"first","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mia","family":"Skj\u00f8dt","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine","family":"Skat-R\u00f8rdam","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00fcnaj","family":"Rakipovski","sequence":"additional","affiliation":[{"name":"CV Research, Global Research, Novo Nordisk A\/S, Novo Nordisk Park 1, 2760 M\u00e5l\u00f8v, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David H.","family":"Ipsen","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6375-8394","authenticated-orcid":false,"given":"Anne Marie V.","family":"Schou-Pedersen","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6514-8407","authenticated-orcid":false,"given":"Jens","family":"Lykkesfeldt","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pernille","family":"Tveden-Nyborg","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,19]]},"reference":[{"key":"ref_1","first-page":"11","article-title":"Global Perspectives on Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis","volume":"15","author":"Younossi","year":"2018","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.metabol.2015.12.012","article-title":"The Multiple-Hit Pathogenesis of Non-Alcoholic Fatty Liver Disease (Nafld)","volume":"65","author":"Buzzetti","year":"2016","journal-title":"Metabolism"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.trsl.2015.10.001","article-title":"Diet-Induced Dyslipidemia Leads to Nonalcoholic Fatty Liver Disease and Oxidative Stress in Guinea Pigs","volume":"168","author":"Birck","year":"2016","journal-title":"Transl. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Caligiuri, A., Gentilini, A., and Marra, F. (2016). Molecular Pathogenesis of Nash. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091575"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1002\/hep.27368","article-title":"Fibrosis Stage Is the Strongest Predictor for Disease-Specific Mortality in Nafld after up to 33 Years of Follow-Up","volume":"61","author":"Ekstedt","year":"2015","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1002\/hep.24268","article-title":"Pathologic Criteria for Nonalcoholic Steatohepatitis: Interprotocol Agreement and Ability to Predict Liver-Related Mortality","volume":"53","author":"Younossi","year":"2011","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1002\/hep.26156","article-title":"Association between Noninvasive Fibrosis Markers and Mortality among Adults with Nonalcoholic Fatty Liver Disease in the United States","volume":"57","author":"Kim","year":"2013","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/ajg.2012.128","article-title":"Diseases American Association for the Study of Liver, Gastroenterology American College of, and Association American Gastroenterological. The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association","volume":"107","author":"Chalasani","year":"2012","journal-title":"Am. J. Gastroenterol."},{"key":"ref_9","first-page":"115","article-title":"2016 Esc\/Eas Guidelines for the Management of Dyslipidaemias","volume":"70","author":"Catapano","year":"2017","journal-title":"Rev. Esp. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) (2016). Easl-Easd-Easo Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease. J. Hepatol., 64, 1388\u20131402.","DOI":"10.1016\/j.jhep.2015.11.004"},{"key":"ref_11","first-page":"75","article-title":"Nonalcoholic Fatty Liver Disease: Epidemiology, Pathogenesis, Natural History, Diagnosis, and Current Treatment Options","volume":"8","author":"Banini","year":"2016","journal-title":"Clin. Med. Insights Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1016\/j.metabol.2008.07.030","article-title":"Efficacy of Atorvastatin for the Treatment of Nonalcoholic Steatohepatitis with Dyslipidemia","volume":"57","author":"Hyogo","year":"2008","journal-title":"Metabolism"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"246","DOI":"10.2174\/1570161115666170621082910","article-title":"Statins: An under-Appreciated Asset for the Prevention and the Treatment of Nafld or Nash and the Related Cardiovascular Risk","volume":"16","author":"Athyros","year":"2018","journal-title":"Curr. Vasc. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1002\/iub.1991","article-title":"Role of Vitamin E in Nonalcoholic Fatty Liver Disease","volume":"71","author":"Nagashimada","year":"2019","journal-title":"IUBMB Life"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.nut.2014.11.018","article-title":"Vitamin E Has a Beneficial Effect on Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials","volume":"31","author":"Sato","year":"2015","journal-title":"Nutrition"},{"key":"ref_16","first-page":"3924","article-title":"Association between Vitamin E and Non-Alcoholic Steatohepatitis: A Meta-Analysis","volume":"8","author":"Xu","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Perumpail, B.J., Li, A.A., John, N., Sallam, S., Shah, N.D., Kwong, W., Cholankeril, G., Kim, D., and Ahmed, A. (2018). The Role of Vitamin E in the Treatment of Nafld. Diseases, 6.","DOI":"10.3390\/diseases6040086"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12986-016-0110-1","article-title":"High-Fat but Not Sucrose Intake Is Essential for Induction of Dyslipidemia and Non-Alcoholic Steatohepatitis in Guinea Pigs","volume":"13","author":"Ipsen","year":"2016","journal-title":"Nutr. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s00438-019-01537-z","article-title":"Molecular Drivers of Non-Alcoholic Steatohepatitis Are Sustained in Mild-to-Late Fibrosis Progression in a Guinea Pig Model","volume":"294","author":"Ipsen","year":"2019","journal-title":"Mol. Genet Genom."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1158\/1055-9965.EPI-07-0639","article-title":"Ascorbate and Dehydroascorbic Acid as Reliable Biomarkers of Oxidative Stress: Analytical Reproducibility and Long-Term Stability of Plasma Samples Subjected to Acidic Deproteinization","volume":"16","author":"Lykkesfeldt","year":"2007","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1111\/jvim.12425","article-title":"Biopterin Status in Dogs with Myxomatous Mitral Valve Disease Is Associated with Disease Severity and Cardiovascular Risk Factors","volume":"28","author":"Reimann","year":"2014","journal-title":"J. Vet. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.nutres.2013.07.006","article-title":"Guinea Pig Ascorbate Status Predicts Tetrahydrobiopterin Plasma Concentration and Oxidation Ratio in Vivo","volume":"33","author":"Mortensen","year":"2013","journal-title":"Nutr. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1093\/bja\/aew410","article-title":"Endothelial Dysfunction in the Early Postoperative Period after Major Colon Cancer Surgery","volume":"118","author":"Ekeloef","year":"2017","journal-title":"Br. J. Anaesth."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/0003-2697(76)90326-2","article-title":"A Fluorometric Method for Determination of Oxidized and Reduced Glutathione in Tissues","volume":"74","author":"Hissin","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1093\/clinchem\/47.9.1725","article-title":"Determination of Malondialdehyde as Dithiobarbituric Acid Adduct in Biological Samples by Hplc with Fluorescence Detection: Comparison with Ultraviolet-Visible Spectrophotometry","volume":"47","author":"Lykkesfeldt","year":"2001","journal-title":"Clin. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/BF02534359","article-title":"A Mild, Rapid, and Efficient Method of Lipid Extraction for Use in Determining Vitamin E\/Lipid Ratios","volume":"20","author":"Burton","year":"1985","journal-title":"Lipids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"And Network Nonalcoholic Steatohepatitis Clinical Research. Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/j.1742-7843.2011.00852.x","article-title":"Chronic Vitamin C Deficiency Does Not Accelerate Oxidative Stress in Ageing Brains of Guinea Pigs","volume":"110","author":"Hasselholt","year":"2012","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of Nafld Development and Therapeutic Strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1053\/j.gastro.2015.04.005","article-title":"Weight Loss through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis","volume":"149","author":"Friedman","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s00535-017-1415-1","article-title":"Current and Future Pharmacological Therapies for Nafld\/Nash","volume":"53","author":"Sumida","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_32","first-page":"1","article-title":"Supplementation with Alpha-Tocopherol and Ascorbic Acid to Nonalcoholic Fatty Liver Disease\u2019s Statin Therapy in Men","volume":"2018","author":"Dimovska","year":"2018","journal-title":"Adv. Pharmacol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1056\/NEJMoa0907929","article-title":"Vitamin E, or Placebo for Nonalcoholic Steatohepatitis","volume":"362","author":"Sanyal","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2159","DOI":"10.37358\/RC.19.6.7296","article-title":"Atorvastatin in the Treatment of Dyslipidemic Patients with Very High Cardiovascular Risk and Nonalcoholic Fatty Liver Disease","volume":"70","author":"Costache","year":"2019","journal-title":"Rev. Chim."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1179552218787502","DOI":"10.1177\/1179552218787502","article-title":"An Evidence-Based Review of Statin Use in Patients with Nonalcoholic Fatty Liver Disease","volume":"11","author":"Sigler","year":"2018","journal-title":"Clin. Med. Insights Gastroenterol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1001\/jama.2011.520","article-title":"And Network Nonalcoholic Steatohepatitis Clinical Research. Effect of Vitamin E or Metformin for Treatment of Nonalcoholic Fatty Liver Disease in Children and Adolescents: The Tonic Randomized Controlled Trial","volume":"305","author":"Lavine","year":"2011","journal-title":"JAMA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1016\/S0140-6736(10)61272-X","article-title":"Greace Study Collaborative Group. Safety and Efficacy of Long-Term Statin Treatment for Cardiovascular Events in Patients with Coronary Heart Disease and Abnormal Liver Tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (Greace) Study: A Post-Hoc Analysis","volume":"376","author":"Athyros","year":"2010","journal-title":"Lancet"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1080\/03007995.2018.1547696","article-title":"Severe Nonalcoholic Steatohepatitis and Type 2 Diabetes: Liver Histology after Weight Loss Therapy in a Randomized Clinical Trial","volume":"35","author":"Oshakbayev","year":"2019","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.cct.2008.09.003","article-title":"And Nash Crn Research Group. Pioglitazone Versus Vitamin E Versus Placebo for the Treatment of Non-Diabetic Patients with Non-Alcoholic Steatohepatitis: Pivens Trial Design","volume":"30","author":"Chalasani","year":"2009","journal-title":"Contemp. Clin. Trials"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"264","DOI":"10.14218\/JCTH.2017.00056","article-title":"Future Pharmacotherapy for Non-Alcoholic Steatohepatitis (Nash): Review of Phase 2 and 3 Trials","volume":"6","author":"Connolly","year":"2018","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/liv.12033","article-title":"Rosuvastatin Ameliorates High-Fat and High-Cholesterol Diet-Induced Nonalcoholic Steatohepatitis in Rats","volume":"33","author":"Okada","year":"2013","journal-title":"Liver Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1046\/j.1365-2036.2001.01083.x","article-title":"Plasma Transforming Growth Factor-Beta1 Level and Efficacy of Alpha-Tocopherol in Patients with Non-Alcoholic Steatohepatitis: A Pilot Study","volume":"15","author":"Hasegawa","year":"2001","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s00441-011-1246-y","article-title":"Tgf-Beta in Progression of Liver Disease","volume":"347","author":"Dooley","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1097\/MOL.0000000000000427","article-title":"Interpreting Lipoproteins in Nonalcoholic Fatty Liver Disease","volume":"28","author":"Nemes","year":"2017","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"569","DOI":"10.7150\/ijbs.14027","article-title":"Dysregulation of the Low-Density Lipoprotein Receptor Pathway Is Involved in Lipid Disorder-Mediated Organ Injury","volume":"12","author":"Zhang","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0022-2275(20)40727-8","article-title":"Lipoprotein Transport, and Regulation of Plasma Concentrations of Vitamin E in Humans","volume":"34","author":"Kayden","year":"1993","journal-title":"J. Lipid Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1079\/BJN20041249","article-title":"The Absorption of Vitamin E Is Influenced by the Amount of Fat in a Meal and the Food Matrix","volume":"92","author":"Jeanes","year":"2004","journal-title":"Br. J. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1093\/ajcn\/nqz172","article-title":"Vitamin E Absorption and Kinetics in Healthy Women, as Modulated by Food and by Fat, Studied Using 2 Deuterium-Labeled Alpha-Tocopherols in a 3-Phase Crossover Design","volume":"110","author":"Traber","year":"2019","journal-title":"Am. J. Clin. 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