{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:10:52Z","timestamp":1790633452643,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81803798"],"award-info":[{"award-number":["81803798"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Intrahepatic cholestasis (IC) occurs when the liver and systemic circulation accumulate bile components, which can then lead to lipid metabolism disorders and oxidative damage. Ginsenosides (GS) are pharmacologically active plant products derived from ginseng that possesses lipid-regulation and antioxidation activities. The purpose of this study was to evaluate the possible protective effects of ginsenosides (GS) on lipid homeostasis disorder and oxidative stress in mice with alpha-naphthylisothiocyanate (ANIT)-induced IC and to investigate the underlying mechanisms. A comprehensive strategy via incorporating pharmacodynamics and molecular biology technology was adopted to investigate the therapeutic mechanisms of GS in ANIT-induced mice liver injury. The effects of GS on cholestasis were studied in mice that had been exposed to ANIT-induced cholestasis. The human HepG2 cell line was then used in vitro to investigate the molecular mechanisms by which GS might improve IC. The gene silencing experiment and liver-specific sirtuin-1 (SIRT1) knockout (SIRT1LKO) mice were used to further elucidate the mechanisms. The general physical indicators were assessed, and biological samples were collected for serum biochemical indexes, lipid metabolism, and oxidative stress-related indicators. Quantitative PCR and H&amp;E staining were used for molecular and pathological analysis. The altered expression levels of key pathway proteins (Sirt1, p-AMPK, Nrf2) were validated by Western blotting. By modulating the AMPK protein expression, GS decreased hepatic lipogenesis, and increased fatty acid \u03b2-oxidation and lipoprotein lipolysis, thereby improving lipid homeostasis in IC mice. Furthermore, GS reduced ANIT-triggered oxidative damage by enhancing Nrf2 and its downstream target levels. Notably, the protective results of GS were eliminated by SIRT1 shRNA in vitro and SIRT1LKO mice in vivo. GS can restore the balance of the lipid metabolism and redox in the livers of ANIT-induced IC models via the SIRT1\/AMPK signaling pathway, thus exerting a protective effect against ANIT-induced cholestatic liver injury.<\/jats:p>","DOI":"10.3390\/nu14193938","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T23:07:55Z","timestamp":1663888075000},"page":"3938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Ginsenosides Restore Lipid and Redox Homeostasis in Mice with Intrahepatic Cholestasis through SIRT1\/AMPK Pathways"],"prefix":"10.3390","volume":"14","author":[{"given":"Guodong","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Tongji Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjiao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Tongji Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Tongji Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui 453199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Tongji Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ximin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Tongji Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congyi","family":"Wang","sequence":"additional","affiliation":[{"name":"The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Tongji Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Tongji Hospital Affiliated Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/nrgastro.2015.12","article-title":"Novel therapeutic targets in primary biliary cirrhosis","volume":"12","author":"Dyson","year":"2015","journal-title":"Nat. Rev. Gastro. Hepat."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"256","DOI":"10.3389\/fphar.2017.00256","article-title":"SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model","volume":"8","author":"Yu","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1002\/hep.22181","article-title":"Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment","volume":"47","author":"Manos","year":"2008","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"217","DOI":"10.5114\/ceh.2018.80122","article-title":"The role of metabolic disorders in the pathogenesis of intrahepatic cholestasis of pregnancy","volume":"4","author":"Bator","year":"2018","journal-title":"Clin. Exp. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1097\/01.AOG.0000189096.94874.9c","article-title":"Plasma Lipid Profiles of Women with intrahepatic cholestasis of pregnancy","volume":"107","author":"Dann","year":"2006","journal-title":"Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S1386-6346(02)00248-6","article-title":"Effect of obstructive jaundice on the regulation of hepatic cholesterol metabolism in the rat. Disappearance of abcg5 and abcg8 mRNA after bile duct ligation","volume":"25","author":"Kamisako","year":"2003","journal-title":"Hepatol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Hu, L.Q., Cui, Y., Qi, Z.Q., Huang, X.P., Cai, L.Y., Zhang, T., Yin, Y.X., Lu, Z.Y., and Xiang, J.Y. (2014). Roles of PPAR\u03b3\/NF-\u03baB Signaling Pathway in the Pathogenesis of Intrahepatic Cholestasis of Pregnancy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087343"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1515\/jpem-2019-0314","article-title":"A novel etiologic factor of highly elevated cholestanol levels: Progressive familial intrahepatic cholestasis","volume":"33","author":"Aynur","year":"2020","journal-title":"J. Pediatric Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2940746","DOI":"10.1155\/2020\/2940746","article-title":"Gentiopicroside Ameliorates Oxidative Stress and Lipid Accumulation through Nuclear Factor Erythroid 2-Related Factor 2 Activation","volume":"2020","author":"Jin","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.freeradbiomed.2020.02.025","article-title":"Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease","volume":"152","author":"Chen","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1007\/s00018-019-03263-6","article-title":"Lipophagy mediated carbohydrate-induced changes of lipid metabolism via oxidative stress, endoplasmic reticulum (ER) stress and ChREBP\/PPAR\u03b3 pathways","volume":"77","author":"Zhao","year":"2020","journal-title":"Cell Mol. Life Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1111\/liv.13344","article-title":"Finding the cure for primary biliary cholangitis-Still waiting","volume":"37","author":"Tanaka","year":"2017","journal-title":"Liver Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.12998\/wjcc.v7.i13.1571","article-title":"Cholestatic liver diseases: An era of emerging therapies","volume":"7","author":"Samant","year":"2019","journal-title":"World J. Clin. Cases"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"110915","DOI":"10.1016\/j.biopha.2020.110915","article-title":"Ginsenosides for the treatment of metabolic syndrome and cardiovascular diseases: Pharmacology and mechanisms","volume":"132","author":"Fan","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Lee, H.S., Lim, S.M., Jung, J.I., Kim, S.M., Lee, J.K., Kim, Y.H., Cha, K.M., Oh, T.K., Moon, J.M., and Kim, T.Y. (2019). Gynostemma Pentaphyllum Extract Ameliorates High-Fat Diet-Induced Obesity in C57BL\/6N Mice by Upregulating SIRT1. Nutrients, 11.","DOI":"10.3390\/nu11102475"},{"key":"ref_16","first-page":"1059","article-title":"Ginsenosides reduce body weight and ameliorate hepatic steatosis in high fat diet-induced obese mice via endoplasmic reticulum stress and p-STAT3 TAT3 signaling","volume":"21","author":"Yao","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1142\/S0192415X20500561","article-title":"Rare Ginsenoside 20(R)-Rg3 Inhibits D-Galactose-Induced Liver and Kidney Injury by Regulating Oxidative Stress-Induced Apoptosis","volume":"48","author":"Li","year":"2020","journal-title":"Am. J. Chin. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.fct.2019.02.032","article-title":"Protective effects of ginsenoside Rk3 against chronic alcohol-induced liver injury in mice through inhibition of inflammation, oxidative stress, and apoptosis","volume":"126","author":"Qu","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1142\/S0192415X17500872","article-title":"Protective Effects of Ginsenosides on 17 [Formula: See text]-Ethynyelstradiol-Induced Intrahepatic Cholestasis via Anti-Oxidative and Anti-Inflammatory Mechanisms in Rats","volume":"45","author":"Xu","year":"2017","journal-title":"Am. J. Chin. Med."},{"key":"ref_20","first-page":"697","article-title":"S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis","volume":"3","author":"Zhang","year":"2020","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1021\/acs.jafc.5b05897","article-title":"Liver Fibrosis Can Be Induced by High Salt Intake through Excess Reactive Oxygen Species (ROS) Production","volume":"64","author":"Guang","year":"2016","journal-title":"J. Agric. Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"119237","DOI":"10.1016\/j.lfs.2021.119237","article-title":"RETRACTED: Echinacoside improves diabetic liver injury by regulating the AMPK\/SIRT1 signaling pathway in db\/db mice","volume":"271","author":"Luo","year":"2021","journal-title":"Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"112326","DOI":"10.1016\/j.jep.2019.112326","article-title":"Flavonoids extracted from mulberry (Morus alba L.) leaf improve skeletal muscle mitochondrial function by activating AMPK in type 2 diabetes","volume":"248","author":"Meng","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.3389\/fphar.2019.01685","article-title":"Baicalin Protects Against 17aEthinylestradiol-Induced Cholestasis via the Sirtuin 1\/Hepatic Nuclear Receptor-1a\/Farnesoid X Receptor Pathway","volume":"10","author":"Yang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_25","first-page":"9913","article-title":"PPAR\u03b1 activation protects against cholestatic liver injury","volume":"7","author":"Zhao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.tibs.2003.11.005","article-title":"The AMP-activated protein kinase cascade\u2014A unifying system for energy control","volume":"29","author":"Carling","year":"2004","journal-title":"Trends. Biochem. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/alcalc\/agv126","article-title":"Melatonin Upregulates the Activity of AMPK and Attenuates Lipid Accumulation in Alcohol-induced Rats","volume":"51","author":"Rui","year":"2015","journal-title":"Alcohol Alcohol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1152\/physrev.00011.2008","article-title":"AMPK in Health and Disease","volume":"89","author":"Steinberg","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.jhep.2006.12.001","article-title":"New perspectives for the treatment of cholestasis: Lessons from basic science applied clinically","volume":"46","author":"Boyer","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1002\/tox.22616","article-title":"Hepatoprotective effect of ginsenoside Rg1 from Panax ginseng on carbon tetrachloride-induced acute liver injury by activating Nrf2 signaling pathway in mice","volume":"33","author":"Ning","year":"2018","journal-title":"Environ. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9128","DOI":"10.1039\/D1FO02081A","article-title":"Hepatoprotective effects of ginsenoside Rk3 in acetaminophen-induced liver injury in mice by activation of autophagy","volume":"12","author":"Qu","year":"2021","journal-title":"Food Funct."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107327","DOI":"10.1016\/j.intimp.2020.107327","article-title":"Hepatoprotection by Ginsenoside Rg1 in alcoholic liver disease","volume":"92","author":"Yang","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"109062","DOI":"10.1016\/j.cbi.2020.109062","article-title":"Ginsenoside Rg1 alleviates ANIT-induced intrahepatic cholestasis in rats via activating farnesoid X receptor and regulating transporters and metabolic enzymes","volume":"324","author":"Xiao","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1002\/hep.27088","article-title":"Role of protein kinase C isoforms in bile formation and cholestasis","volume":"60","author":"Anwer","year":"2014","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1093\/toxsci\/kfp020","article-title":"ANIT-Induced Intrahepatic Cholestasis Alters Hepatobiliary Transporter Expression via Nrf2-Dependent and Independent Signaling","volume":"108","author":"Tanaka","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1080\/00498254.2018.1467065","article-title":"Lipidomics reveal Aryl hydrocarbon receptor (Ahr)-regulated lipid metabolic pathway in alpha-naphthyl isothiocyanate(ANIT)-induced intrahepatic cholestasis","volume":"49","author":"Wang","year":"2019","journal-title":"Xenobiotica"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2147\/JIR.S348866","article-title":"Ginsenoside Rb1 Protects Against Diabetic Cardiomyopathy by Regulating the Adipocytokine Pathway","volume":"15","author":"Zhang","year":"2022","journal-title":"J. Inflamm. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.tem.2013.12.001","article-title":"SIRT1 and other sirtuins in metabolism","volume":"25","author":"Chang","year":"2014","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1038\/ijo.2008.116","article-title":"AMPK: A key regulator of energy balance in the single cell and the whole organism","volume":"32","author":"Hardie","year":"2008","journal-title":"Int. J. Obes."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1748-1716.2009.01970.x","article-title":"AMP-activated protein kinase in the regulation of hepatic energy metabolism: From physiology to therapeutic perspectives","volume":"196","author":"Viollet","year":"2009","journal-title":"Acta Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s10571-016-0355-2","article-title":"Sirt1: Role Under the Condition of Ischemia\/Hypoxia","volume":"37","author":"Meng","year":"2017","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"78804","DOI":"10.18632\/oncotarget.12860","article-title":"Nuclear transcription factor Nrf2 suppresses prostate cancer cells growth and migration through upregulating ferroportin","volume":"7","author":"Xue","year":"2016","journal-title":"Oncotarget"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1021\/jacs.0c10836","article-title":"A SIRT1 Activator, Ginsenoside Rc, Promotes Energy Metabolism in Cardiomyocytes and Neurons","volume":"143","author":"Huang","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e12627","DOI":"10.1111\/cpr.12627","article-title":"Ginsenoside Rb3 provides protective effects against cisplatin-induced nephrotoxicity via regulation of AMPK-\/mTOR-mediated autophagy and inhibition of apoptosis In Vitro and In Vivo","volume":"52","author":"Xing","year":"2019","journal-title":"Cell Prolif."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"932165","DOI":"10.1155\/2012\/932165","article-title":"Ginsenoside-Rg1 Protects the Liver against Exhaustive Exercise-Induced Oxidative Stress in Rats","volume":"2012","author":"Korivi","year":"2012","journal-title":"Evid. Based Complement Alternat. Med."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/19\/3938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:37:43Z","timestamp":1760143063000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/19\/3938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,22]]},"references-count":45,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["nu14193938"],"URL":"https:\/\/doi.org\/10.3390\/nu14193938","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,22]]}}}