{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T04:58:50Z","timestamp":1777265930796,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"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":["81400791"],"award-info":[{"award-number":["81400791"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease worldwide. Caspase 8 and FADD-like apoptosis regulator (CFLAR) has been identified as a potent factor in mitigating non-alcoholic steatohepatitis (NASH) by inhibiting the N-terminal dimerization of apoptosis signal-regulating kinase 1 (ASK1). While arginine methyltransferase 1 (PRMT1) was previously reported to be associated with increased hepatic glucose production, its involvement in hepatic lipid metabolism remains largely unexplored. The interaction between PRMT1 and CFLAR and the methylation of CFLAR were verified by Co-IP and immunoblotting assays. Recombinant adenoviruses were generated for overexpression or knockdown of PRMT1 in hepatocytes. The role of PRMT1 in NAFLD was investigated in normal and high-fat diet-induced obese mice. In this study, we found a significant upregulation of PRMT1 and downregulation of CFLAR after 48h of fasting, while the latter significantly rebounded after 12h of refeeding. The expression of PRMT1 increased in the livers of mice fed a methionine choline-deficient (MCD) diet and in hepatocytes challenged with oleic acid (OA)\/palmitic acid (PA). Overexpression of PRMT1 not only inhibited the expression of genes involved in fatty acid oxidation (FAO) and promoted the expression of genes involved in fatty acid synthesis (FAS), resulting in increased triglyceride accumulation in primary hepatocytes, but also enhanced the gluconeogenesis of primary hepatocytes. Conversely, knockdown of hepatic PRMT1 significantly alleviated MCD diet-induced hepatic lipid metabolism abnormalities and liver injury in vivo, possibly through the upregulation of CFLAR protein levels. Knockdown of PRMT1 suppressed the expression of genes related to FAS and enhanced the expression of genes involved in FAO, causing decreased triglyceride accumulation in OA\/PA-treated primary hepatocytes in vitro. Although short-term overexpression of PRMT1 had no significant effect on hepatic triglyceride levels under physiological conditions, it resulted in increased serum triglyceride and fasting blood glucose levels in normal C57BL\/6J mice. More importantly, PRMT1 was observed to interact with and methylate CFLAR, ultimately leading to its ubiquitination-mediated protein degradation. This process subsequently triggered the activation of c-Jun N-terminal kinase 1 (JNK1) and lipid deposition in primary hepatocytes. Together, these results suggested that PRMT1-mediated methylation of CFLAR plays a critical role in hepatic lipid metabolism. Targeting PRMT1 for drug design may represent a promising strategy for the treatment of NAFLD.<\/jats:p>","DOI":"10.3390\/ijms25147897","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T09:14:53Z","timestamp":1721380493000},"page":"7897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Regulatory Impact of CFLAR Methylation Modification on Liver Lipid Metabolism"],"prefix":"10.3390","volume":"25","author":[{"given":"Chen","family":"Ye","sequence":"first","affiliation":[{"name":"National & Local Joint Engineering Research Center of High throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, College of Health Science and Engineering, Hubei University, Wuhan 430062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Jiang","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of High throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, College of Health Science and Engineering, Hubei University, Wuhan 430062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Hu","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of High throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, College of Health Science and Engineering, Hubei University, Wuhan 430062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jichao","family":"Liang","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of High throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, College of Health Science and Engineering, Hubei University, Wuhan 430062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Chen","sequence":"additional","affiliation":[{"name":"National & Local Joint Engineering Research Center of High throughput Drug Screening Technology, Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, College of Health Science and Engineering, Hubei University, Wuhan 430062, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/ncp.10449","article-title":"Evolution of NAFLD and its management","volume":"35","author":"Mundi","year":"2020","journal-title":"Nutr. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41575-020-00381-6","article-title":"Global epidemiology of NAFLD-related HCC: Trends, predictions, risk factors and prevention","volume":"18","author":"Huang","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/liv.13302","article-title":"Therapies in non-alcoholic steatohepatitis (NASH)","volume":"37","author":"Oseini","year":"2017","journal-title":"Liver Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3497","DOI":"10.1007\/s10620-021-07203-y","article-title":"Environmental toxicants and NAFLD: A neglected yet significant relationship","volume":"67","author":"Rajak","year":"2022","journal-title":"Dig. Dis. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"G99","DOI":"10.1152\/ajpgi.00168.2022","article-title":"Nutritional, pharmacological, and environmental programming of NAFLD in early life","volume":"324","year":"2023","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"105484","DOI":"10.1016\/j.phrs.2021.105484","article-title":"Epigenetics in NAFLD\/NASH: Targets and therapy","volume":"167","author":"Sodum","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nm.4290","article-title":"Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates","volume":"23","author":"Wang","year":"2017","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.biopha.2018.09.089","article-title":"Effect of silibinin on CFLAR-JNK pathway in oleic acid-treated HepG2 cells","volume":"108","author":"Liu","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.mam.2016.11.008","article-title":"Epigenetics in non-alcoholic fatty liver disease","volume":"54","author":"Lee","year":"2017","journal-title":"Mol. Asp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1038\/s41467-018-03999-y","article-title":"Epigenetic landscape influences the liver cancer genome architecture","volume":"9","author":"Hama","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.2337\/db18-0537","article-title":"Epigenetics and epigenomics: Implications for diabetes and obesity","volume":"67","author":"Rosen","year":"2018","journal-title":"Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1002\/tcr.201800082","article-title":"Mechanisms and inhibitors of histone arginine methylation","volume":"18","author":"Fulton","year":"2018","journal-title":"Chem. Rec."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.molcel.2016.11.003","article-title":"Arginine methylation: The coming of age","volume":"65","author":"Blanc","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"33009","DOI":"10.1074\/jbc.M704349200","article-title":"Alternative splicing yields protein arginine methyltransferase 1 isoforms with distinct activity, substrate specificity, and subcellular localization","volume":"282","author":"Goulet","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.gene.2019.02.072","article-title":"Novel alternative splice variants of the human protein arginine methyltransferase 1 (PRMT1) gene, discovered using next-generation sequencing","volume":"699","author":"Adamopoulos","year":"2019","journal-title":"Gene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s13277-010-0153-2","article-title":"Clinical evaluation of PRMT1 gene expression in breast cancer","volume":"32","author":"Mathioudaki","year":"2011","journal-title":"Tumor Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1002\/ijc.25366","article-title":"Dysregulation of PRMT1 and PRMT6, Type I arginine methyltransferases, is involved in various types of human cancers","volume":"128","author":"Yoshimatsu","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s13402-019-00435-1","article-title":"PRMT1 promotes pancreatic cancer growth and predicts poor prognosis","volume":"43","author":"Song","year":"2020","journal-title":"Cell. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1038\/s41388-020-01617-0","article-title":"PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer","volume":"40","author":"Yin","year":"2021","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1002\/hep.25809","article-title":"Protein arginine methyltransferase 1 regulates hepatic glucose production in a FoxO1-dependent manner","volume":"56","author":"Choi","year":"2012","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.jhep.2014.06.032","article-title":"Thioredoxin-interacting protein mediates hepatic lipogenesis and inflammation via PRMT1 and PGC-1\u03b1 regulation in vitro and in vivo","volume":"61","author":"Park","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1210\/en.2019-00504","article-title":"Protein Arginine Methyltransferase 1 Interacts with PGC1 \u03b1 and Modulates Thermogenic Fat Activation","volume":"160","author":"Qiao","year":"2019","journal-title":"Endocrinology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14863","DOI":"10.1096\/fj.202001061R","article-title":"A critical role for hepatic protein arginine methyltransferase 1 isoform 2 in glycemic control","volume":"34","author":"Ma","year":"2020","journal-title":"FASEB J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.7150\/thno.63824","article-title":"Hepatic PRMT1 ameliorates diet-induced hepatic steatosis via induction of PGC1\u03b1","volume":"12","author":"Xu","year":"2022","journal-title":"Theranostics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9456","DOI":"10.1021\/bi800984s","article-title":"Substrate profiling of PRMT1 reveals amino acid sequences that extend beyond the \u201cRGG\u201d paradigm","volume":"47","author":"Wooderchak","year":"2008","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1074\/mcp.RA119.001625","article-title":"Deep protein methylation profiling by combined chemical and immunoaffinity approaches reveals novel PRMT1 targets","volume":"18","author":"Hartel","year":"2019","journal-title":"Mol. Cell. Proteom."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9111","DOI":"10.1038\/s41598-019-45585-2","article-title":"Hepatocyte PRMT1 protects from alcohol induced liver injury by modulating oxidative stress responses","volume":"9","author":"Zhao","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"108151","DOI":"10.1016\/j.intimp.2021.108151","article-title":"Silencing miR-181b-5p upregulates PIAS1 to repress oxidative stress and inflammatory response in rats with alcoholic fatty liver disease through inhibiting PRMT1","volume":"101","author":"Wang","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhang, X.Z., Li, L., Li, Y.W., Li, Z., Zhai, W.Q., Sun, Q.Z., Yang, X.J., Roth, M., and Lu, S.M. (2021). mTOR regulates PRMT1 expression and mitochondrial mass through STAT1 phosphorylation in hepatic cell. Biochim. Biophys. Acta (BBA)-Mol. Cell Res., 1868.","DOI":"10.1016\/j.bbamcr.2021.119017"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.exer.2009.09.004","article-title":"PRMT-1 and DDAHs-induced ADMA upregulation is involved in ROS-and RAS-mediated diabetic retinopathy","volume":"89","author":"Chen","year":"2009","journal-title":"Exp. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.2337\/db20-1050","article-title":"Depletion of Prmt1 in adipocytes impairs glucose homeostasis in diet-induced obesity","volume":"70","author":"Choi","year":"2021","journal-title":"Diabetes"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.21037\/apm-21-417","article-title":"Abnormalities of the PRMT1-ADMA-DDAH1 metabolism axis and probucol treatment in diabetic patients and diabetic rats","volume":"10","author":"Mei","year":"2021","journal-title":"Ann. Palliat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s11010-016-2758-2","article-title":"MCD diet-induced steatohepatitis is associated with alterations in asymmetric dimethylarginine (ADMA) and its transporters","volume":"419","author":"Berardo","year":"2016","journal-title":"Mol. Cell. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1002\/hep.29587","article-title":"Protein arginine methyl transferase 1 and Jumonji C domain containing protein 6 dependent arginine methylation regulate hepatocyte nuclear factor 4 alpha expression and hepatocyte proliferation in mice","volume":"67","author":"Zhao","year":"2018","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.tem.2019.08.008","article-title":"NAFLD and atherosclerosis: Two sides of the same dysmetabolic coin?","volume":"30","author":"Hovingh","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Alshawsh, M.A., Alsalahi, A., Alshehade, S.A., Saghir, S.A.M., Ahmeda, A.F., Al Zarzour, R.H., and Mahmoud, A.M. (2022). A comparison of the gene expression profiles of non-alcoholic fatty liver disease between animal models of a high-fat diet and methionine-choline-deficient diet. Molecules, 27.","DOI":"10.3390\/molecules27030858"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1016\/j.jhep.2017.02.001","article-title":"\u03b27-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis","volume":"66","author":"Drescher","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.clinre.2014.08.014","article-title":"Nonalcoholic fatty liver disease (NAFLD) without insulin resistance: Is it different?","volume":"39","author":"Singh","year":"2015","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bernhardt, P., Kratzer, W., Schmidberger, J., Graeter, T., and Gruener, B. (2018). Laboratory parameters in lean NAFLD: Comparison of subjects with lean NAFLD with obese subjects without hepatic steatosis. BMC Res. Notes, 11.","DOI":"10.1186\/s13104-018-3212-1"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1007\/s12072-021-10143-4","article-title":"The epidemiology of NAFLD and lean NAFLD in Japan: A meta-analysis with individual and forecasting analysis, 1995\u20132040","volume":"15","author":"Ito","year":"2021","journal-title":"Hepatol. Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e21230","DOI":"10.1096\/fj.202000683R","article-title":"CDKN2A deregulation in fatty liver disease and its accelerative role in the process of lipogenesis","volume":"35","author":"Zhang","year":"2021","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.apsb.2019.02.006","article-title":"Silibinin ameliorates hepatic lipid accumulation and oxidative stress in mice with non-alcoholic steatohepatitis by regulating CFLAR-JNK pathway","volume":"9","author":"Liu","year":"2019","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Thiebaut, C., Eve, L., Poulard, C., and Le Romancer, M. (2021). Structure, activity, and function of prmt1. Life, 11.","DOI":"10.3390\/life11111147"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Rasineni, K., Jordan, C.W., Thomes, P.G., Kubik, J.L., Staab, E.M., Sweeney, S.A., Talmon, G.A., Donohue, T.M., McNiven, M.A., and Kharbanda, K.K. (2021). Contrasting effects of fasting on liver-adipose axis in alcohol-associated and non-alcoholic fatty liver. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.625352"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e14009","DOI":"10.7717\/peerj.14009","article-title":"Hepatic metabolite responses to 4-day complete fasting and subsequent refeeding in rats","volume":"10","author":"Sui","year":"2022","journal-title":"PeerJ"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.jhep.2003.09.020","article-title":"The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance","volume":"40","author":"Rinella","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s12094-020-02422-7","article-title":"ADMA mediates gastric cancer cell migration and invasion via Wnt\/\u03b2-catenin signaling pathway","volume":"23","author":"Guo","year":"2021","journal-title":"Clin. Transl. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/hep.24402","article-title":"Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis","volume":"54","author":"Qiao","year":"2011","journal-title":"Hepatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jhep.2012.10.024","article-title":"MicroRNA-29a-c decrease fasting blood glucose levels by negatively regulating hepatic gluconeogenesis","volume":"58","author":"Liang","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ye, D.E., Yang, X.F., Ren, L.W., Lu, H.S., Sun, Y., Lin, H., Tan, L.B., Wang, N., Nguyen, G., and Bader, M. (2021). (Pro) renin receptor inhibition reduces plasma cholesterol and triglycerides but does not attenuate atherosclerosis in atherosclerotic mice. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.725203"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7897\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:19:28Z","timestamp":1760109568000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7897"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,19]]},"references-count":50,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25147897"],"URL":"https:\/\/doi.org\/10.3390\/ijms25147897","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,19]]}}}