Hepatocyte-specific METTL3 ablation by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), resulted in acute liver failure (ALF) and postnatal lethality.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38656880", "kind": "science-record", "revision": 3, "content_hash": "sha256:86fcd9d363d55099e8f0dfcfd28f1d563a864f4c41c8fcd4f20d39a7e781f2d3", "created_at": "2026-11-01T19:20:37Z", "updated_at": "2026-11-01T21:33:00Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Hepatocyte-specific METTL3 ablation by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), resulted in acute liver failure (ALF) and postnatal lethality.", "doi": "10.18632/aging.205753", "pmid": "38656880", "authors": ["Shihao Huang", "Yingchun Li", "Bingjie Wang", "Zhihao Zhou", "Yonglong Li", "Lingjun Shen", "Jinge Cong", "Liuxin Han", "Xudong Xiang", "Jiawei Xia", "Danhua He", "Zhanlin Zhao", "Ying Zhou", "Qiwen Li", "Guanqi Dai", "Hanzhang Shen", "Taoyan Lin", "Aibing Wu", "Junshuang Jia", "Dong Xiao", "Jing Li", "Wentao Zhao", "Xiaolin Lin"], "journal": "Aging", "year": 2024, "abstract": "AIM: In 2019, to examine the functions of METTL3 in liver and underlying mechanisms, we generated mice with hepatocyte-specific METTL3 homozygous knockout (METTL3Δhep) by simultaneously crossing METTL3fl/fl mice with Alb-iCre mice (GPT) or Alb-Cre mice (JAX), respectively. In this study, we explored the potential reasons why hepatocyte-specific METTL3 homozygous disruption by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), resulted in acute liver failure (ALF) and then postnatal lethality.\nMAIN METHODS: Mice with hepatocyte-specific METTL3 knockout were generated by simultaneously crossing METTL3fl/fl mice with Alb-iCre mice (GPT; Strain No. T003814) purchased from the GemPharmatech Co., Ltd., (Nanjing, China) or with Alb-Cre mice (JAX; Strain No. 003574) obtained from The Jackson Laboratory, followed by combined-phenotype analysis. The publicly available RNA-sequencing data deposited in the NCBI Gene Expression Omnibus (GEO) database under the accession No.: GSE198512 (postnatal lethality), GSE197800 (postnatal survival) and GSE176113 (postnatal survival) were mined to explore the potential reasons why hepatocyte-specific METTL3 homozygous deletion by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), leads to ALF and then postnatal lethality.\nKEY FINDINGS: Firstly, we observed that hepatocyte-specific METTL3 homozygous deficiency by Alb-iCre mice (GPT) or by Alb-Cre mice (JAX) caused liver injury, abnormal lipid accumulation and apoptosis. Secondly, we are surprised to find that hepatocyte-specific METTL3 homozygous deletion by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), led to ALF and then postnatal lethality. Our findings clearly demonstrated that METTL3Δhep mice (GPT), which are about to die, exhibited the severe destruction of liver histological structure, suggesting that METTL3Δhep mice (GPT) nearly lose normal liver function, which subsequently contributes to ALF, followed by postnatal lethality. Finally, we unexpectedly found that as the compensatory growth responses of hepatocytes to liver injury induced by METTL3Δhep (GPT), the proliferation of METTL3Δhep hepatocytes (GPT), unlike METTL3Δhep hepatocytes (JAX), was not evidenced by the significant increase of Ki67-positive hepatocytes, not accompanied by upregulation of cell-cycle-related genes. Moreover, GO analysis revealed that upregulated genes in METTL3Δhep livers (GPT), unlike METTL3Δhep livers (JAX), are not functionally enriched in terms associated with cell cycle, cell division, mitosis, microtubule cytoskeleton organization, spindle organization, chromatin segregation and organization, and nuclear division, consistent with the loss of compensatory proliferation of METTL3Δhep hepatocytes (GPT) observed in vivo. Thus, obviously, the loss of the compensatory growth capacity of METTL3Δhep hepatocytes (GPT) in response to liver injury might contribute to, at least partially, ALF and subsequently postnatal lethality of METTL3Δhep mice (GPT).\nSIGNIFICANCE: These findings from this study and other labs provide strong evidence that these phenotypes (i.e., ALF and postnatal lethality) of METTL3Δhep mice (GPT) might be not the real functions of METTL3, and closely related with Alb-iCre mice (GPT), suggesting that we should remind researchers to use Alb-iCre mice (GPT) with caution to knockout gene in hepatocytes in vivo.", "claims": [{"id": "claim-method", "statement": "Two-tailed Student’s t-test was employed to compare data between two independent groups.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38656880", "locator": "sections[22] \"Statistical analysis\" paragraph 2", "quote": "Two-tailed Student’s t-test was employed to compare data between two independent groups."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The RNA-seq data sets reported in the studies of the labs of Prof. Qi Zhang (The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China) [17], Prof. Detian Yuan (School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China) [16] and Prof. Kalpana Ghoshal (College of Medicine, The Ohio State University, Columbus, Ohio) [20] have been deposited in the NCBI Gene Expression Omnibus (GEO) database under the accession No. GSE198512, GSE197800 and GSE176113, respectively.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38656880", "locator": "sections[23] \"Data availability\" paragraph 2", "quote": "The RNA-seq data sets reported in the studies of the labs of Prof. Qi Zhang (The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China) [17], Prof. Detian Yuan (School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China) [16] and Prof. Kalpana Ghoshal (College of Medicine, The Ohio State University, Columbus, Ohio) [20] have been deposited in the NCBI Gene Expression Omnibus (GEO) database under the accession No. GSE198512, GSE197800 and GSE176113, respectively."}], "state": "complete"}, {"id": "claim-target-result", "statement": "GO analysis showed that upregulated genes in METTL3Δhep livers (GPT) lacked enrichment for cell-cycle and division-related processes, consistent with a loss of compensatory hepatocyte proliferation that may contribute to acute liver failure and postnatal lethality.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:38656880", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Moreover, GO analysis revealed that upregulated genes in METTL3Δhep livers (GPT), unlike METTL3Δhep livers (JAX), are not functionally enriched in terms associated with cell cycle, cell division, mitosis, microtubule cytoskeleton organization, spindle organization, chromatin segregation and organization, and nuclear division, consistent with the loss of compensatory proliferation of METTL3Δhep hepatocytes (GPT) observed in vivo."}, {"asset": "source:pmid:38656880", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Thus, obviously, the loss of the compensatory growth capacity of METTL3Δhep hepatocytes (GPT) in response to liver injury might contribute to, at least partially, ALF and subsequently postnatal lethality of METTL3Δhep mice (GPT)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "GO analysis showed that upregulated genes in METTL3Δhep livers (GPT) lacked enrichment for cell-cycle and division-related processes, consistent with a loss of compensatory hepatocyte proliferation that may contribute to acute liver failure and postnatal lethality.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:38656880"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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