{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T12:34:47Z","timestamp":1761395687286,"version":"build-2065373602"},"reference-count":74,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,24]],"date-time":"2020-02-24T00:00:00Z","timestamp":1582502400000},"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":["534-180010235, 2662017PY013"],"award-info":[{"award-number":["534-180010235, 2662017PY013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatic disorders have been increasing in recent years because of high carbohydrate diets. Hepatocytes depend mainly on the basal autophagy to maintain hepatic glucose\/lipid homeostasis in mammals. However, the regulatory mechanisms of autophagy in hepatic energy metabolism are still unknown in fish species. Accordingly, mutant zebrafish lines of autophagy-related genes beclin1 and atg7 were generated by CRISPR\/Cas9 gene-editing technology. Interestingly, unlike atg7+\/\u2212, male beclin1+\/\u2212 zebrafish displayed liver defects in the morphology and histology, including abnormal hepatocyte proliferation, hemorrhagic and inflammatory phenotypes. A significant decrease in hepatocyte glycogen and an increase in hepatocyte lipids were detected in the histological assay that coincidence with the hepatic gene expression. Meanwhile, loss of heterozygosity for beclin1 creates a suitable microenvironment for hepatic tumorigenesis via phosphorylation of Akt kinase, which in turn affects liver autophagy. The reduction in autophagy activity in male beclin1+\/\u2212 liver leads to a disturbance in the glucose\/lipid metabolism and negatively regulates apoptosis accompanied by the induction of cellular proliferation and acute inflammatory response. Our findings highlight an important role of beclin1 in zebrafish liver development and energy metabolism, suggesting the crucial role of autophagy in maintaining homeostasis of the nutrient metabolism in fish species.<\/jats:p>","DOI":"10.3390\/ijms21041533","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T04:21:26Z","timestamp":1582604486000},"page":"1533","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Strategy of Hepatic Metabolic Defects Induced by beclin1 Heterozygosity in Adult Zebrafish"],"prefix":"10.3390","volume":"21","author":[{"given":"Suzan Attia","family":"Mawed","sequence":"first","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"He","sequence":"additional","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Mei","sequence":"additional","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/cphy.c130024","article-title":"Energy metabolism in the liver","volume":"4","author":"Rui","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1126\/science.1193497","article-title":"Autophagy and metabolism","volume":"330","author":"Rabinowitz","year":"2010","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1053\/j.gastro.2015.09.042","article-title":"Regulation of Liver Metabolism by Autophagy","volume":"150","author":"Cuervo","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.jgg.2019.03.008","article-title":"HDAC6 regulates lipid droplet turnover in response to nutrient deprivation via p62-mediated selective autophagy","volume":"46","author":"Yan","year":"2019","journal-title":"J. Genet. Genomics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.aca.2017.11.005","article-title":"Lipid metabolism in mouse embryonic fibroblast cells in response to autophagy induced by nutrient stress","volume":"1037","author":"Shen","year":"2018","journal-title":"Anal. Chim. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.jhep.2015.10.008","article-title":"Induction of autophagy improves hepatic lipid metabolism in glucose-6-phosphatase deficiency","volume":"64","author":"Farah","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"110521","DOI":"10.1016\/j.cbpa.2019.06.021","article-title":"Inhibited autophagy impairs systemic nutrient metabolism in Nile tilapia","volume":"236","author":"Han","year":"2019","journal-title":"Comp. Biochem. Physiol. A Mol. Integr. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/cr.2013.168","article-title":"The machinery of macroautophagy","volume":"24","author":"Feng","year":"2014","journal-title":"Cell Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1016\/j.cellsig.2014.08.019","article-title":"The role of PI3K\/AKT\/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration","volume":"26","year":"2014","journal-title":"Cell Signal."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1016\/j.cub.2011.11.034","article-title":"Mechanisms of autophagosome biogenesis","volume":"22","author":"Rubinsztein","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15077","DOI":"10.1073\/pnas.2436255100","article-title":"Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor","volume":"100","author":"Yue","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","first-page":"1581","article-title":"Allele Loss from Chromosome-17 in Ovarian-Cancer","volume":"5","author":"Russell","year":"1990","journal-title":"Oncogene"},{"key":"ref_13","first-page":"2069","article-title":"Early Loss of Heterozygosity on 17q in Ovarian-Cancer","volume":"7","author":"Eccles","year":"1992","journal-title":"Oncogene"},{"key":"ref_14","first-page":"2624","article-title":"Detection of Frequent Allelic Loss on Proximal Chromosome-17q in Sporadic Breast-Carcinoma Using Microsatellite Length Polymorphisms","volume":"52","author":"Futreal","year":"1992","journal-title":"Cancer Res."},{"key":"ref_15","first-page":"3382","article-title":"Detailed Deletion Mapping of Chromosome 17q in Ovarian and Breast Cancers\u20142-Cm Region on 17q21.3 Often and Commonly Deleted in Tumors","volume":"53","author":"Saito","year":"1993","journal-title":"Cancer Res."},{"key":"ref_16","first-page":"1002","article-title":"Loss of heterozygosity of the BRCA1 and other loci on chromosome 17q in human prostate cancer","volume":"55","author":"Gao","year":"1995","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/45257","article-title":"Induction of autophagy and inhibition of tumorigenesis by beclin 1","volume":"402","author":"Liang","year":"1999","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1172\/JCI20039","article-title":"Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene","volume":"112","author":"Qu","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"41280","DOI":"10.1038\/srep41280","article-title":"Males develop faster and more severe hepatocellular carcinoma than females in kras(V12) transgenic zebrafish","volume":"7","author":"Li","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ctrv.2003.07.007","article-title":"PI3K\/Akt signalling pathway and cancer","volume":"30","author":"Casado","year":"2004","journal-title":"Cancer Treat. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ejca.2017.06.003","article-title":"New liver cancer biomarkers: PI3K\/AKT\/mTOR pathway members and eukaryotic translation initiation factors","volume":"83","author":"Krassnig","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/j.1365-2184.2012.00845.x","article-title":"Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis","volume":"45","author":"Ouyang","year":"2012","journal-title":"Cell Prolif."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1101\/gad.1599207","article-title":"Autophagy: Process and function","volume":"21","author":"Mizushima","year":"2007","journal-title":"Genes Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis: A review of programmed cell death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1136\/gutjnl-2011-301364","article-title":"Apoptosis, necrosis and necroptosis: Cell death regulation in the intestinal epithelium","volume":"62","author":"Gunther","year":"2013","journal-title":"Gut"},{"key":"ref_26","first-page":"3448","article-title":"Crosstalk between apoptosis, necrosis and autophagy","volume":"1833","author":"Nikoletopoulou","year":"2013","journal-title":"BBA-Mol. Cell Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.4161\/cc.20424","article-title":"Inhibition of autophagy impairs tumor cell invasion in an organotypic model","volume":"11","author":"Macintosh","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/cdd.2013.17","article-title":"Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis","volume":"20","author":"Hanel","year":"2013","journal-title":"Cell Death Differ."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/j.cell.2009.11.026","article-title":"Mutant p53 Drives Invasion by Promoting Integrin Recycling","volume":"139","author":"Muller","year":"2009","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"173","DOI":"10.4308\/hjb.21.4.173","article-title":"Correlation Between Akt and p53 Protein Expression and Chemoradiotherapy Response in Cervical Cancer Patients","volume":"21","author":"Kurnia","year":"2014","journal-title":"Hayati J. Biosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3056","DOI":"10.4161\/cc.7.19.6751","article-title":"Mutant p53 protein localized in the cytoplasm inhibits autophagy","volume":"7","author":"Morselli","year":"2008","journal-title":"Cell Cycle"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.semcdb.2019.05.011","article-title":"Wild type- and mutant p53 proteins in mitochondrial dysfunction: Emerging insights in cancer disease","volume":"98","author":"Blandino","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2157","DOI":"10.1038\/sj.onc.1210302","article-title":"TP53 mutations in human cancers: Functional selection and impact on cancer prognosis and outcomes","volume":"26","author":"Petitjean","year":"2007","journal-title":"Oncogene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ccr.2006.06.001","article-title":"Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis","volume":"10","author":"Degenhardt","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1089\/ars.2010.3485","article-title":"Autophagy Shapes Inflammation","volume":"14","author":"Fesus","year":"2011","journal-title":"Antioxid. Redox Sign."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.cyto.2015.07.027","article-title":"Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions","volume":"76","author":"Zhou","year":"2015","journal-title":"Cytokine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.ccr.2009.02.003","article-title":"IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer (vol 15, pg 103, 2009)","volume":"15","author":"Grivennikov","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1016\/j.ejca.2005.08.016","article-title":"The role of IL-6 and STAT3 in inflammation and cancer","volume":"41","author":"Hodge","year":"2005","journal-title":"Eur. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"ra58","DOI":"10.1126\/scisignal.2001180","article-title":"HCMV-Encoded Chemokine Receptor US28 Mediates Proliferative Signaling Through the IL-6-STAT3 Axis","volume":"3","author":"Slinger","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"912","DOI":"10.21037\/tcr.2018.06.17","article-title":"The targeting of endoglin on vascular endothelial cells affects the infiltration of M2 macrophages into the breast cancer microenvironment by modulating the interleukin-6 (IL-6) level","volume":"7","author":"Zhang","year":"2018","journal-title":"Transl. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3740","DOI":"10.1158\/0008-5472.CAN-13-3182","article-title":"Autophagy Inhibition by Sustained Overproduction of IL6 Contributes to Arsenic Carcinogenesis","volume":"74","author":"Qi","year":"2014","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15701","DOI":"10.1038\/srep15701","article-title":"IL-6 Inhibits Starvation-induced Autophagy via the STAT3\/Bcl-2 Signaling Pathway","volume":"5","author":"Qin","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/nbt1169","article-title":"Conservation of gene expression signatures between zebrafish and human liver tumors and tumor progression","volume":"24","author":"Lam","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9933","DOI":"10.3748\/wjg.v22.i45.9933","article-title":"Reprogramming of glucose metabolism in hepatocellular carcinoma: Progress and prospects","volume":"22","author":"Shang","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7124","DOI":"10.3390\/ijms15057124","article-title":"SREBP-1 Has a Prognostic Role and Contributes to Invasion and Metastasis in Human Hepatocellular Carcinoma","volume":"15","author":"Li","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.bbagen.2012.04.001","article-title":"CD36 promotes adipocyte differentiation and adipogenesis","volume":"1820","author":"Christiaens","year":"2012","journal-title":"BBA-Gen. Subj."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Zhao, T., Wu, K., Hogstrand, C., Xu, Y.H., Chen, G.H., Wei, C.C., and Luo, Z. (2019). Lipophagy mediated carbohydrate-induced changes of lipid metabolism via oxidative stress, endoplasmic reticulum (ER) stress and ChREBP\/PPARgamma pathways. Cell Mol. Life Sci.","DOI":"10.1007\/s00018-019-03263-6"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrc839","article-title":"The phosphatidylinositol 3-Kinase AKT pathway in human cancer","volume":"2","author":"Vivanco","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/leu.2008.26","article-title":"Contributions of the Raf\/MEK\/ERK, PI3K\/PTEN\/Akt\/mTOR and Jak\/STAT pathways to leukemia","volume":"22","author":"Steelman","year":"2008","journal-title":"Leukemia"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1083\/jcb.200412022","article-title":"Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice","volume":"169","author":"Komatsu","year":"2005","journal-title":"J. Cell Biol"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1101\/gad.2016211","article-title":"Autophagy-deficient mice develop multiple liver tumors","volume":"25","author":"Takamura","year":"2011","journal-title":"Genes Dev."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Rohatgi, R. (2015). Autophagy-Independent Role for Beclin 1 in the Regulation of Growth Factor Receptor Signaling: A Dissertation. [Ph.D. Thesis, University of Massachusetts Medical School].","DOI":"10.1038\/onc.2014.454"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5921","DOI":"10.1074\/jbc.M110.179101","article-title":"Akt Requires Glucose Metabolism to Suppress Puma Expression and Prevent Apoptosis of Leukemic T Cells","volume":"286","author":"Coloff","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.3748\/wjg.v10.i11.1547","article-title":"Gender difference in clinicopathologic features and survival of patients with hepatocellular carcinoma","volume":"10","author":"Tangkijvanich","year":"2004","journal-title":"World J. Gastroenterol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1046\/j.1440-1746.2003.02936.x","article-title":"Longer survival in female than male with hepatocellular carcinoma","volume":"18","author":"Dohmen","year":"2003","journal-title":"J. Gastroen. Hepatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1007\/s11427-014-4797-9","article-title":"Genetic basis and biotechnological manipulation of sexual dimorphism and sex determination in fish","volume":"58","author":"Mei","year":"2015","journal-title":"Sci. China Life Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ccr.2009.01.002","article-title":"gp130-Mediated Stat3 Activation in Enterocytes Regulates Cell Survival and Cell-Cycle Progression during Colitis-Associated Tumorigenesis","volume":"15","author":"Bollrath","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e1030539","DOI":"10.1080\/23723556.2015.1030539","article-title":"An autophagy-independent function for Beclin 1 in cancer","volume":"3","author":"Rohatgi","year":"2016","journal-title":"Mol. Cell Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/1476-4598-12-152","article-title":"Tumor glycolysis as a target for cancer therapy: Progress and prospects","volume":"12","author":"Geschwind","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jhep.2008.07.036","article-title":"Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma","volume":"50","author":"Yamashita","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.plipres.2013.08.005","article-title":"Lipogenesis and lipolysis: The pathways exploited by the cancer cells to acquire fatty acids","volume":"52","author":"Zaidi","year":"2013","journal-title":"Prog. Lipid Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1158\/2159-8290.CD-12-0107","article-title":"CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues","volume":"2","author":"DeFilippis","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1177\/1947601911409747","article-title":"Inflammation and p53: A Tale of Two Stresses","volume":"2","author":"Gudkov","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1111\/j.1356-9597.2004.00750.x","article-title":"The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8","volume":"9","author":"Sugawara","year":"2004","journal-title":"Genes Cells"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0076-6879(08)03612-4","article-title":"Monitoring Autophagic Degradation of P62\/Sqstm1","volume":"452","author":"Bjorkoy","year":"2009","journal-title":"Method Enzymol."},{"key":"ref_67","unstructured":"Westerfield, M. (1995). The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish (Brachydanio Rerio), University of Oregon Press."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"274","DOI":"10.4103\/0974-7788.76794","article-title":"Understanding survival analysis: Kaplan-Meier estimate","volume":"1","author":"Goel","year":"2010","journal-title":"Int. J. Ayurveda Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4358","DOI":"10.1073\/pnas.1010210108","article-title":"The serine-threonine kinase LKB1 is essential for survival under energetic stress in zebrafish","volume":"108","author":"Wang","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"111807","DOI":"10.18632\/oncotarget.22910","article-title":"Leucine mediates autophagosome-lysosome fusion and improves sperm motility by activating the PI3K\/Akt pathway","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1016\/j.scib.2018.08.012","article-title":"A novel PDZ domain-containing gene is essential for male sex differentiation and maintenance in yellow catfish (Pelteobagrus fulvidraco)","volume":"63","author":"Dan","year":"2018","journal-title":"Sci. Bull."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1023\/A:1009631424351","article-title":"False-positive apoptosis signal in mouse kidney and liver detected with TUNEL assay","volume":"5","author":"Pulkkanen","year":"2000","journal-title":"Apoptosis"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1002\/cyto.a.23287","article-title":"Quantification of large scale DNA organization for predicting prostate cancer recurrence","volume":"91a","author":"MacAulay","year":"2017","journal-title":"Cytom. Part A"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nbt.2450","article-title":"Differential analysis of gene regulation at transcript resolution with RNA-seq","volume":"31","author":"Trapnell","year":"2013","journal-title":"Nat. Biotechnol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1533\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:01:11Z","timestamp":1760173271000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1533"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,24]]},"references-count":74,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ijms21041533"],"URL":"https:\/\/doi.org\/10.3390\/ijms21041533","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2020,2,24]]}}}