title: An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization.
abstract: Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Because ER stress is known to induce M2 macrophage polarization, we examined whether Nogo-B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). M1 and M2 phenotypes were assessed in relation to Nogo-B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild-type (WT) and Nogo-B knockout (KO) mice fed a control or Lieber-DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo-B KO mice were assessed for M1 and M2 activation. A significant positive correlation was observed between Nogo-B positive Kupffer cells and disease severity in ALD patients (n = 30, r = 0.66, P = 0.048). Furthermore, Nogo-B-positive Kupffer cells were correlated with M1 activation (inducible nitric oxide synthase) (r = 0.50, P = 0.05) and negatively with markers of M2 status (CD163) (r = -0.48, P = 0.07) in these patients. WT mice exhibited significantly increased liver injury (P < 0.05) and higher hepatic triglyceride levels (P < 0.01) compared with Nogo-B KO mice in response to chronic ethanol feeding. Nogo-B in Kupffer cells promoted M1 polarization, whereas absence of Nogo-B increased ER stress and M2 polarization in Kupffer cells.
  
  
  
  Nogo-B is permissive of M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo-B in Kupffer cells may represent a new therapeutic target for ALD. (Hepatology 2017;65:1720-1734).
authors.affiliation: Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.|Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Park
authors.affiliation: Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.|Transplantation Surgery Center, Third Xiangya Hospital, Central South University, Changsha, P.R. China.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Shao
authors.affiliation: Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.|Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
authors.forename: Moon Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
authors.forename: Soon Koo
authors.initials: SK
authors.lastname: Baik
authors.affiliation: Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
authors.forename: Mee Yon
authors.initials: MY
authors.lastname: Cho
authors.affiliation: Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.
authors.forename: Teruo
authors.initials: T
authors.lastname: Utsumi
authors.affiliation: The Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Satoh
authors.affiliation: Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.
authors.forename: Xinsho
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.|VA CT Healthcare System, West Haven, CT.
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
authors.affiliation: Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Iwakiri
mesh_terms: D000818:Animals; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism*; D008108:Liver Diseases, Alcoholic / Q000209:etiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000070798:Nogo Proteins / Q000378:metabolism*
chemical_list: D000070798:Nogo Proteins