title: Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice.
abstract: The role(s) of the epidermal growth factor receptor (EGFR) in hepatocytes is unknown. We generated a murine hepatocyte specific-EGFR knockout (KO) model to evaluate how loss of hepatocellular EGFR expression affects processes such as EGF clearance, circulating EGF concentrations, and liver regeneration following 70% resection or CCl4-induced centrilobular injury. We were able to disrupt EGFR expression effectively in hepatocytes and showed that the ability of EGF and heregulin (HRG) to phosphorylate EGFR and ERBB3, respectively, required EGFR. Loss of hepatocellular EGFR impaired clearance of exogenous EGF from the portal circulation but paradoxically resulted in reduced circulating levels of endogenous EGF. This was associated with decreased submandibular salivary gland production of EGF. EGFR disruption did not result in increased expression of other ERBB proteins or Met, except in neonatal mice. Liver regeneration following 70% hepatectomy revealed a mild phenotype, with no change in cyclin D1 expression and slight differences in cyclin A expression compared with controls. Peak 5-bromo-2'-deoxyuridine labeling was shifted from 36 to 48 h. Centrilobular damage and regenerative response induced by carbon tetrachloride (CCl4) were identical in the KO and wild-type mice. In contrast, loss of Met increased CCl4-induced necrosis and delayed regeneration. Although loss of hepatocellular EGFR alone did not have an effect in this model, EGFR-Met double KOs displayed enhanced necrosis and delayed liver regeneration compared with Met KOs alone. This suggests that EGFR and Met may partially compensate for the loss of the other, although other compensatory mechanisms can be envisioned.
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee; lawrence.a.scheving@vanderbilt.edu.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Scheving
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Xiuqi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Mary C
authors.initials: MC
authors.lastname: Stevenson
authors.affiliation: Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas; and Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas.
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee; Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Diabetes Center, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: William E
authors.initials: WE
authors.lastname: Russell
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism* / Q000502:physiology; D008115:Liver Regeneration; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D019925:Cyclin A; D020890:Neuregulin-1; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D002251:Carbon Tetrachloride; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D020893:Receptor, ErbB-3
keywords: EGFR; Met; carbon tetrachloride; hepatectomy; liver; submandibular gland