title: SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration.
abstract: After significant injury, the liver must maintain homeostasis during the regenerative process. We hypothesized the existence of mechanisms to limit hepatocyte proliferation after injury to maintain metabolic and synthetic function. A screen for candidates revealed suppressor of cytokine signaling 2 (SOCS2), an inhibitor of growth hormone (GH) signaling, was strongly induced after partial hepatectomy. Using genetic deletion and administration of various factors we investigated the role of SOCS2 during liver regeneration. SOCS2 preserves liver function by restraining the first round of hepatocyte proliferation after partial hepatectomy by preventing increases in growth hormone receptor (GHR) via ubiquitination, suppressing GH pathway activity. At later times, SOCS2 enhances hepatocyte proliferation by modulating a decrease in serum insulin-like growth factor 1 (IGF-1) that allows GH release from the pituitary. SOCS2, therefore, plays a dual role in modulating the rate of hepatocyte proliferation. In particular, this is the first demonstration of an endogenous mechanism to limit hepatocyte proliferation after injury.
authors.affiliation: From the Transplant Center, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Ryota
authors.initials: R
authors.lastname: Masuzaki
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Sophia
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138.
authors.forename: M Todd
authors.initials: MT
authors.lastname: Valerius
authors.affiliation: From the Transplant Center, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsugawa
authors.affiliation: From the Transplant Center, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Oya
authors.affiliation: From the Transplant Center, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Ray
authors.affiliation: From the Transplant Center, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, seth.karp@vanderbilt.edu.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Karp
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D006498:Hepatectomy / Q000009:adverse effects; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000037:antagonists & inhibitors*; D008099:Liver / Q000166:cytology / Q000502:physiology* / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D011986:Receptors, Somatotropin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D011986:Receptors, Somatotropin; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone
keywords: growth hormone; insulin-like growth factor (IGF); liver injury; regeneration; socs2; ubiquitylation (ubiquitination)