{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:17:48Z","timestamp":1789654668433,"version":"4.0.1"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,30]],"date-time":"2021-05-30T00:00:00Z","timestamp":1622332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Fundamental Research Funds for the Central Universities","award":["2632020ZD16"],"award-info":[{"award-number":["2632020ZD16"]}]},{"name":"the National Natural Science Foundation of China","award":["81773826"],"award-info":[{"award-number":["81773826"]}]},{"name":"the National Natural Science Foundation of China","award":["81703608"],"award-info":[{"award-number":["81703608"]}]},{"name":"Sanming Project of Medicine in Shenzhen","award":["SZSM201801060"],"award-info":[{"award-number":["SZSM201801060"]}]},{"name":"the Project of State Key Laboratory of Natural Medicines of China Pharmaceutical University","award":["SKLNMZZ202001"],"award-info":[{"award-number":["SKLNMZZ202001"]}]},{"name":"the National Key New Drug Creation Special Program of China","award":["2017ZX09304021"],"award-info":[{"award-number":["2017ZX09304021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis.<\/jats:p>","DOI":"10.3390\/ijms22115884","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:22:15Z","timestamp":1622420535000},"page":"5884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8956-8924","authenticated-orcid":false,"given":"Li","family":"Lu","sequence":"first","affiliation":[{"name":"Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0147-1608","authenticated-orcid":false,"given":"Kun","family":"Hao","sequence":"additional","affiliation":[{"name":"Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Hong","sequence":"additional","affiliation":[{"name":"Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3922-4998","authenticated-orcid":false,"given":"Jinwei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjiao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheying","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Molecular Therapeutics & Formulation, School of Pharmacy, University Park Campus, The University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangji","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Peng","sequence":"additional","affiliation":[{"name":"Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Henne, W.M., Reese, M.L., and Goodman, J.M. (2018). The assembly of lipid droplets and their roles in challenged cells. EMBO J., 37.","DOI":"10.15252\/embj.201898947"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.cmet.2009.03.011","article-title":"As a Matter of Fat","volume":"10","author":"Brookheart","year":"2009","journal-title":"Cell Metab."},{"key":"ref_3","first-page":"1","article-title":"Triglyceride Metabolism in the Liver","volume":"8","author":"Cohen","year":"2017","journal-title":"Compr. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.physbeh.2007.11.049","article-title":"Lipid accumulation in non-adipose tissue and lipotoxicity","volume":"94","year":"2008","journal-title":"Physiol. Behav."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1248\/cpb.c18-00954","article-title":"Membrane States of Saturated Glycerophospholipids: A Thermodynamic Study of Bilayer Phase Transitions","volume":"67","author":"Matsuki","year":"2019","journal-title":"Chem. Pharm. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.ecl.2008.09.002","article-title":"Intracellular Lipid Accumulation in Liver and Muscle and the Insulin Resistance Syndrome","volume":"37","author":"Garvey","year":"2008","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/978-3-319-48382-5_12","article-title":"Insulin Resistance, Obesity and Lipotoxicity","volume":"960","author":"Sezer","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1038\/s41419-020-03003-w","article-title":"Understanding lipotoxicity in NAFLD pathogenesis: Is CD36 a key driver?","volume":"11","author":"Rada","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.metabol.2016.02.014","article-title":"Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease","volume":"65","author":"Mota","year":"2016","journal-title":"Metabolism"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Neuschwander-Tetri, B.A. (2017). Non-alcoholic fatty liver disease. BMC Med., 15.","DOI":"10.1186\/s12916-017-0806-8"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"127","DOI":"10.5152\/tjg.2014.7675","article-title":"Nonalcoholic fatty liver disease: Diagnosis, pathogenesis, and management","volume":"25","author":"Basaranoglu","year":"2014","journal-title":"Turk. J. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.biopha.2018.06.060","article-title":"Magnesium isoglycyrrhizinate ameliorates liver fibrosis and hepatic stellate cell activation by regulating ferroptosis signaling pathway","volume":"106","author":"Sui","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"173314","DOI":"10.1016\/j.ejphar.2020.173314","article-title":"Magnesium isoglycyrrhizinate alleviates fructose-induced liver oxidative stress and inflammatory injury through suppressing NOXs","volume":"883","author":"Yang","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","first-page":"2020","article-title":"Magnesium isoglycyrrhizinate has hepatoprotective effects in an oxaliplatininduced model of liver injury","volume":"42","author":"Zou","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1111\/liv.14204","article-title":"Efficacy and safety of magnesium isoglycyrrhizinate injection in patients with acute drug-induced liver injury: A phase II trial","volume":"39","author":"Wang","year":"2019","journal-title":"Liver Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1159\/000235873","article-title":"Prevention of Free Fatty Acid-Induced Hepatic Lipotoxicity in HepG2 Cells by Magnesium Isoglycyrrhizinate in vitro","volume":"84","author":"Cheng","year":"2009","journal-title":"Pharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3892\/ijmm.2016.2603","article-title":"Protective role of magnesium isoglycyrrhizinate in non-alcoholic fatty liver disease and the associated molecular mechanisms","volume":"38","author":"Xu","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1136\/gutjnl-2018-318146","article-title":"miRNAs and NAFLD: From pathophysiology to therapy","volume":"68","author":"Gjorgjieva","year":"2019","journal-title":"Gut"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, B., He, X., Jia, W., and Li, H. (2017). Novel Applications of Metabolomics in Personalized Medicine: A Mini-Review. Molecules, 22.","DOI":"10.3390\/molecules22071173"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11306-005-1102-8","article-title":"Metabolomics: Building on a century of biochemistry to guide human health","volume":"1","author":"German","year":"2005","journal-title":"Metabolomics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40246-018-0134-x","article-title":"Beyond genomics: Understanding exposotypes through metabolomics","volume":"12","author":"Rattray","year":"2018","journal-title":"Hum. Genom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.cell.2010.11.033","article-title":"Lipidomics: New Tools and Applications","volume":"143","author":"Wenk","year":"2010","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1146\/annurev-biochem-060713-035324","article-title":"Lipidomics: Analysis of the Lipid Composition of Cells and Subcellular Organelles by Electrospray Ionization Mass Spectrometry","volume":"83","year":"2014","journal-title":"Annu. Rev. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/978-3-319-48382-5_8","article-title":"What Is Lipotoxicity?","volume":"960","author":"Engin","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"40514","DOI":"10.18632\/oncotarget.17121","article-title":"Quantification of cell cycle kinetics by EdU (5-ethynyl-2\u2032-deoxyuridine)-coupled-fluorescence-intensity analysis","volume":"8","author":"Pereira","year":"2017","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13394","DOI":"10.1073\/pnas.1712555114","article-title":"Metabolic activity induces membrane phase separation in endoplasmic reticulum","volume":"114","author":"Shen","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1194\/jlr.M700592-JLR200","article-title":"Identification of a novel sn-glycerol-3-phosphate acyltransferase isoform, GPAT4, as the enzyme deficient in Agpat6\u2212\/\u2212 mice","volume":"49","author":"Nagle","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1194\/jlr.M500556-JLR200","article-title":"Agpat6--a novel lipid biosynthetic gene required for triacylglycerol production in mammary epithelium","volume":"47","author":"Beigneux","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10048","DOI":"10.1074\/jbc.M708151200","article-title":"AGPAT6 is a novel microsomal glycerol-3-phosphate acyltransferase","volume":"283","author":"Chen","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.tem.2010.01.009","article-title":"Gluttony, sloth and the metabolic syndrome: A roadmap to lipotoxicity","volume":"21","author":"Unger","year":"2010","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1097\/MOL.0000000000000056","article-title":"How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver?","volume":"25","author":"Wang","year":"2014","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S311","DOI":"10.1194\/jlr.R800049-JLR200","article-title":"Membrane phospholipid synthesis and endoplasmic reticulum function","volume":"50","author":"Fagone","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_33","first-page":"1151","article-title":"Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response","volume":"1861","author":"Sargsyan","year":"2016","journal-title":"Biochim. Biophys. Acta BBA Mol. Cell Biol. Lipids"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1194\/jlr.R067595","article-title":"The role of ER stress in lipid metabolism and lipotoxicity","volume":"57","author":"Han","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/sj.cdd.4401373","article-title":"Roles of CHOP\/GADD153 in endoplasmic reticulum stress","volume":"11","author":"Oyadomari","year":"2004","journal-title":"Cell Death Differ."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:11Z","timestamp":1760162951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,30]]},"references-count":35,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115884"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115884","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,30]]}}}