{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T11:14:34Z","timestamp":1789470874805,"version":"build-2803163510"},"reference-count":30,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,28]],"date-time":"2021-11-28T00:00:00Z","timestamp":1638057600000},"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":["[82070596]"],"award-info":[{"award-number":["[82070596]"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Beijing of China","award":["7202145"],"award-info":[{"award-number":["7202145"]}]},{"name":"the State Key Laboratory of Proteomics","award":["SKLP-K201404"],"award-info":[{"award-number":["SKLP-K201404"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute liver injury shares a common feature of hepatocytes death, immune system disorders, and cellular stress. Hepassocin (HPS) is a hepatokine that has ability to promote hepatocytes proliferation and to protect rats from D-galactose (D-Gal)- or carbon tetrachloride (CCl4)-induced liver injury by stimulating hepatocytes proliferation and preventing the high mortality rate, hepatocyte death, and hepatic inflammation. In this paper, we generated a pharmaceutical-grade recombinant human HPS using mammalian cells expression system and evaluated the effects of HPS administration on the pathogenesis of acute liver injury in monkey and mice. In the model mice of D-galactosamine (D-GalN) plus lipopolysaccharide (LPS)-induced liver injury, HPS treatment significantly reduced hepatocyte death and inflammation response, and consequently attenuated the development of acute liver failure. In the model monkey of D-GalN-induced liver injury, HPS administration promoted hepatocytes proliferation, prevented hepatocyte apoptosis and oxidation stress, and resulted in amelioration of liver injury. Furthermore, the primary pharmacokinetic study showed natural HPS possesses favorable pharmacokinetics; the acute toxicity study indicated no significant changes in behavioral, clinical, or histopathological parameters of HPS-treated mice, implying the clinical potential of HPS. Our results suggest that exogenous HPS has protective effects on acute liver injury in both mice and monkeys. HPS or HPS analogues and mimetics may provide novel drugs for the treatment of acute liver injury.<\/jats:p>","DOI":"10.3390\/ijms222312886","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T23:22:28Z","timestamp":1638314548000},"page":"12886","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Recombinant Human HPS Protects Mice and Nonhuman Primates from Acute Liver Injury"],"prefix":"10.3390","volume":"22","author":[{"given":"Yang","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huali","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Institute of Lifeomics, Beijing 102206, China"},{"name":"School of Basic Medical Sciences, An Hui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofang","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Institute of Lifeomics, Beijing 102206, China"},{"name":"Institute of Life Sciences, He Bei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Institute of Lifeomics, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihou","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Institute of Lifeomics, Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taoyun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guifang","family":"Dou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chutse","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China"},{"name":"Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Institute of Lifeomics, Beijing 102206, China"},{"name":"School of Basic Medical Sciences, An Hui Medical University, Hefei 230032, China"},{"name":"Institute of Life Sciences, He Bei University, Baoding 071002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1159\/000444557","article-title":"Acute Liver Failure\u2014It\u2019s Just a Matter of Cell Death","volume":"34","author":"Sowa","year":"2016","journal-title":"Dig. Dis."},{"key":"ref_2","first-page":"24","article-title":"Pathophysiology of Acute Liver Failure","volume":"35","author":"Dong","year":"2020","journal-title":"Nutr. Clin. Pract. Off. Publ. Am. Soc. Parenter. Enter. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1055\/s-0038-1673372","article-title":"Acute Liver Failure","volume":"39","author":"Rajaram","year":"2018","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0167-4781(01)00249-4","article-title":"Molecular cloning and functional expression analysis of a cDNA for human hepassocin, a liver-specific protein with hepatocyte mitogenic activity","volume":"1520","author":"Hara","year":"2001","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1136\/gut.2008.171124","article-title":"Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure","volume":"59","author":"Li","year":"2010","journal-title":"Gut"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Demchev, V., Malana, G., Vangala, D., Stoll, J., Desai, A., Kang, H.W., Li, Y., Nayeb-Hashemi, H., Niepel, M., and Cohen, D.E. (2013). Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058084"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/lipd.12099","article-title":"Unsaturated Fatty Acids Increase the Expression of Hepassocin through a Signal Transducer and Activator of Transcription 3-Dependent Pathway in HepG2 Cells","volume":"53","author":"Cheng","year":"2018","journal-title":"Lipids"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Han, N.K., Jung, M.G., Jeong, Y.J., Son, Y., Han, S.C., Park, S., Lim, Y.B., Lee, Y.J., Kim, S.H., and Park, S.C. (2019). Plasma Fibrinogen-Like 1 as a Potential Biomarker for Radiation-Induced Liver Injury. Cells, 8.","DOI":"10.3390\/cells8091042"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.mce.2017.10.014","article-title":"Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle","volume":"470","author":"Jung","year":"2018","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.bbrc.2007.11.069","article-title":"Fibrinogen-like protein 1, a hepatocyte derived protein is an acute phase reactant","volume":"365","author":"Liu","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/j.jhep.2013.06.004","article-title":"The role of hepassocin in the development of non-alcoholic fatty liver disease","volume":"59","author":"Wu","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.2174\/1871530318666180716100543","article-title":"Overexpression of Hepassocin in Diabetic Patients with Nonalcoholic Fatty Liver Disease May Facilitate Increased Hepatic Lipid Accumulation","volume":"19","author":"Abdelmoemen","year":"2019","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1210\/jc.2016-3287","article-title":"The Hepatic Protection Effects of Hepassocin in Hyperglycemic Crisis","volume":"102","author":"Ou","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","first-page":"831","article-title":"Protective effect of mesenchymal stem cell-conditioned medium on hepatic cell apoptosis after acute liver injury","volume":"6","author":"Xagorari","year":"2013","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.3892\/mmr.2015.3660","article-title":"Bone marrow-derived mesenchymal stem cells attenuate acute liver injury and regulate the expression of fibrinogen-like-protein 1 and signal transducer and activator of transcription 3","volume":"12","author":"Zou","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1038\/sj.onc.1207306","article-title":"LFIRE-1\/HFREP-1, a liver-specific gene, is frequently downregulated and has growth suppressor activity in hepatocellular carcinoma","volume":"23","author":"Yan","year":"2004","journal-title":"Oncogene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13335","DOI":"10.1074\/jbc.M806393200","article-title":"Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma","volume":"284","author":"Yu","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.bbrc.2015.07.078","article-title":"Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development","volume":"465","author":"Desai","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S417","DOI":"10.33549\/physiolres.933506","article-title":"In vitro and in vivo experimental hepatotoxic models in liver research: Applications to the assessment of potential hepatoprotective drugs","volume":"65","author":"Farghali","year":"2016","journal-title":"Physiol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"17399","DOI":"10.3748\/wjg.v20.i46.17399","article-title":"Hybrid bioartificial liver support in cynomolgus monkeys with D-galactosamine-induced acute liver failure","volume":"20","author":"Zhang","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.pep.2013.09.014","article-title":"Functional expression of hepassocin in Escherichia coli using SUMO fusion partner and molecular chaperones","volume":"92","author":"Wang","year":"2013","journal-title":"Protein Expr. Purif."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.cell.2018.11.010","article-title":"Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3","volume":"176","author":"Wang","year":"2019","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.bbrc.2006.09.018","article-title":"Hepatocyte-derived fibrinogen-related protein-1 is associated with the fibrin matrix of a plasma clot","volume":"350","author":"Rijken","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1016\/j.cell.2018.11.012","article-title":"Inflammatory Cytokine TNFalpha Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture","volume":"175","author":"Peng","year":"2018","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1016\/j.bbrc.2020.10.003","article-title":"NLRP3 is dispensable for d-galactosamine\/lipopolysaccharide-induced acute liver failure","volume":"533","author":"Zhang","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1016\/j.cellsig.2014.04.013","article-title":"Hepassocin activates the EGFR\/ERK cascade and induces proliferation of L02 cells through the Src-dependent pathway","volume":"26","author":"Gao","year":"2014","journal-title":"Cell. Signal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D792","DOI":"10.1093\/nar\/gkp1005","article-title":"PrimerBank: A resource of human and mouse PCR primer pairs for gene expression detection and quantification","volume":"38","author":"Spandidos","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D1144","DOI":"10.1093\/nar\/gkr1013","article-title":"PrimerBank: A PCR primer database for quantitative gene expression analysis, 2012 update","volume":"40","author":"Wang","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"29751","DOI":"10.1074\/jbc.M114.565960","article-title":"Fibroblast growth factor 21 is regulated by the IRE1alpha-XBP1 branch of the unfolded protein response and counteracts endoplasmic reticulum stress-induced hepatic steatosis","volume":"289","author":"Jiang","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12886\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:37:06Z","timestamp":1760168226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12886"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,28]]},"references-count":30,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222312886"],"URL":"https:\/\/doi.org\/10.3390\/ijms222312886","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,28]]}}}