{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Fetuin‐B (FETUB) appears to be a multifunctional hepatokine/adipokine that plays diverse roles in both reproductive and metabolic–cardiovascular physiology. One of its best‐characterized functions is in female fertility, where fetuin‐B acts as a specific inhibitor of the cortical granule protease ovastacin. By preventing premature cleavage of zona pellucida protein 2, fetuin‐B preserves zona pellucida permeability until fertilization occurs, a function that is reflected by reduced fertilization rates and altered zona mechanics when its levels are insufficient (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In metabolic and cardiovascular contexts, circulating fetuin‐B is consistently found to be upregulated in states of hepatic steatosis, type 2 diabetes mellitus, gestational diabetes, polycystic ovary syndrome, and coronary artery disease. Elevated fetuin‐B levels are associated with parameters of insulin resistance and adverse glucose metabolism, although recent genetic analyses suggest that these associations might not be directly causal."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": " Furthermore, elevated fetuin‐B has been implicated in modulating vascular cell behavior – for example by enhancing monocyte and vascular smooth muscle cell migration, matrix metalloproteinase activation, and changes in TGF‐β receptor signaling that may contribute to plaque instability and in‐stent restenosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond these disease associations, circulating fetuin‐B levels are responsive to physiologic interventions. For instance, resistance and aerobic training lower serum fetuin‐B in individuals with type 2 diabetes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", while vitamin D signaling directly downregulates hepatocellular FETUB synthesis, linking vitamin D deficiency to pediatric obesity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Moreover, shifts in fetuin‐B concentrations have been observed following weight‐loss surgery and appear to correlate with improved metabolic profiles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In reproductive medicine, altered fetuin‐B levels in both serum and follicular fluid correlate with fertilization outcomes in in vitro fertilization settings and may further interact with thyroid autoimmunity to impact embryo quality."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " In addition, preliminary evidence points to a potential tumor‐suppressive role in certain cancers, as overexpression of fetuin‐B inhibited cell migration and promoted apoptosis via downregulation of PI3K/AKT signaling in prostate cancer cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", and its genomic vicinity has been linked to angiogenic and tumor‐related processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore fetuin‐B’s dual role as an essential fertility factor—by preventing premature zona pellucida hardening—and as an important modulator of metabolic and cardiovascular function. Its regulation by lifestyle factors and vitamin D, together with its emerging role as a biomarker for metabolic disorders and cardiovascular risk, highlights fetuin‐B as a promising target for diagnostic and therapeutic strategies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eileen Dietzel, Jennifer Wessling, Julia Floehr, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fetuin-B, a liver-derived plasma protein is essential for fertilization."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2013.03.001"}], "href": "https://doi.org/10.1016/j.devcel.2013.03.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23562279"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23562279"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hagen Körschgen, Michael Kuske, Konstantin Karmilin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intracellular activation of ovastacin mediates pre-fertilization hardening of the zona pellucida."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gax040"}], "href": "https://doi.org/10.1093/molehr/gax040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28911209"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28911209"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Tibisay Guevara, Hagen Körschgen, Anna Cuppari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The C-terminal region of human plasma fetuin-B is dispensable for the raised-elephant-trunk mechanism of inhibition of astacin metallopeptidases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-019-51095-y"}], "href": "https://doi.org/10.1038/s41598-019-51095-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31604990"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31604990"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Carlo Schmitz, Seyedeh Zeynab Sadr, Hagen Körschgen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E-modulus of the oocyte is a non-destructive measure of zona pellucida hardening."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reproduction (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/REP-21-0122"}], "href": "https://doi.org/10.1530/REP-21-0122"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34320465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34320465"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Andreas Peter, Marketa Kovarova, Harald Staiger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The hepatokines fetuin-A and fetuin-B are upregulated in the state of hepatic steatosis and may differently impact on glucose homeostasis in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Endocrinol Metab (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpendo.00262.2017"}], "href": "https://doi.org/10.1152/ajpendo.00262.2017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29138227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29138227"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jinzhou Zhu, Xingyong Wan, Yuming Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum fetuin B level increased in subjects of nonalcoholic fatty liver disease: a case-control study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrine (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12020-016-1112-5"}], "href": "https://doi.org/10.1007/s12020-016-1112-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27628583"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27628583"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Susan Kralisch, Annett Hoffmann, Ulrike Lössner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of the novel adipokines/ hepatokines fetuin A and fetuin B in gestational diabetes mellitus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Metabolism (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.metabol.2016.11.017"}], "href": "https://doi.org/10.1016/j.metabol.2016.11.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28183456"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28183456"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Zhibin Li, Changqin Liu, Xiulin Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common genetic variants in the FETUB locus, genetically predicted fetuin-B levels, and risk of insulin resistance in obese Chinese adults."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Medicine (Baltimore) (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MD.0000000000009234"}], "href": "https://doi.org/10.1097/MD.0000000000009234"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29390354"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29390354"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Seung Hyo Jung, Kyung-Jong Won, Kang Pa Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The serum protein fetuin-B is involved in the development of acute myocardial infarction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Sci (Lond) (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/CS20140462"}], "href": "https://doi.org/10.1042/CS20140462"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25671698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25671698"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Wenjuan Xing, Yanzhen Tan, Kaifeng Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Cell Cardiol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yjmcc.2020.03.002"}], "href": "https://doi.org/10.1016/j.yjmcc.2020.03.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32147518"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32147518"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Seung Hyo Jung, Donghyen Lee, Hengzhe Jin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fetuin-B regulates vascular plaque rupture via TGF-β receptor-mediated Smad pathway in vascular smooth muscle cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pflugers Arch (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00424-020-02385-2"}], "href": "https://doi.org/10.1007/s00424-020-02385-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32382986"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32382986"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Jingyuan Hou, Qiaoting Deng, Sudong Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plasma Proteome Profiling of Patients With In-stent Restenosis by Tandem Mass Tag-Based Quantitative Proteomics Approach."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Cardiovasc Med (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fcvm.2022.793405"}], "href": "https://doi.org/10.3389/fcvm.2022.793405"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35265678"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35265678"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "A Keihanian, H Arazi, M Kargarfard "}, {"type": "b", "children": [{"type": "t", "text": "Effects of aerobic versus resistance training on serum fetuin-A, fetuin-B, and fibroblast growth factor-21 levels in male diabetic patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Physiol Int (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1556/2060.106.2019.01"}], "href": "https://doi.org/10.1556/2060.106.2019.01"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30888221"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30888221"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Gillian E Walker, Antonia Follenzi, Valentina Bruscaggin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fetuin B links vitamin D deficiency and pediatric obesity: Direct negative regulation by vitamin D."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Steroid Biochem Mol Biol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jsbmb.2018.04.009"}], "href": "https://doi.org/10.1016/j.jsbmb.2018.04.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29684480"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29684480"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Parisa Savedoroudi, Tue Bjerg Bennike, Kenneth Kastaniegaard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum proteome changes and accelerated reduction of fat mass after laparoscopic gastric plication in morbidly obese patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Proteomics (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jprot.2019.05.001"}], "href": "https://doi.org/10.1016/j.jprot.2019.05.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31054967"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31054967"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Xiaorui Hu, Fengyi Mo, Qing Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Correlation of fetuin-B concentrations in serum and follicular fluid with outcomes of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "in vitro"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " fertilization]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhejiang Da Xue Xue Bao Yi Xue Ban (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3785/j.issn.1008-9292.2017.06.10"}], "href": "https://doi.org/10.3785/j.issn.1008-9292.2017.06.10"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29039171"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29039171"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Rui Zhang, Feifei Cheng, Wei Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Relationships among Plasma Fetuin-B, Thyroid Autoimmunity, and Fertilization Rate In Vitro Fertilization and Embryo Transfer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Endocrinol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2022/9961253"}], "href": "https://doi.org/10.1155/2022/9961253"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35340679"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35340679"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Kai Zhan, Rui Liu, Hang Tong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fetuin B overexpression suppresses proliferation, migration, and invasion in prostate cancer by inhibiting the PI3K/AKT signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomed Pharmacother (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biopha.2020.110689"}], "href": "https://doi.org/10.1016/j.biopha.2020.110689"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32892030"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32892030"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Ssucheng J Hsu, Hiroki Nagase, Allan Balmain "}, {"type": "b", "children": [{"type": "t", "text": "Identification of Fetuin-B as a member of a cystatin-like gene family on mouse chromosome 16 with tumor suppressor activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genome (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1139/g04-043"}], "href": "https://doi.org/10.1139/g04-043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15499407"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15499407"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Mingzhu Lin, Changqin Liu, Yongwen Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fetuin-B Links Nonalcoholic Fatty Liver Disease to Chronic Kidney Disease in Obese Chinese Adults: A Cross-Sectional Study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Nutr Metab (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000499843"}], "href": "https://doi.org/10.1159/000499843"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30965331"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30965331"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Agnieszka Adamska, Aleksandra Maria Polak, Anna Krentowska, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased serum fetuin-B concentration is associated with HOMA-β and indices of liver steatosis in women with polycystic ovary syndrome: a pilot study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocr Connect (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/EC-19-0243"}], "href": "https://doi.org/10.1530/EC-19-0243"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31307012"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31307012"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Martina Sattlecker, Steven J Kiddle, Stephen Newhouse, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Alzheimers Dement (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jalz.2013.09.016"}], "href": "https://doi.org/10.1016/j.jalz.2013.09.016"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24768341"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24768341"}]}]}]}