An Endoplasmic Reticulum Protein, Nogo-B, Facilitates Alcoholic Liver Disease Through Regulation of Kupffer Cell Polarization

作者：Park, Jin-Kyu; Shao, Mingjie; Kim, Moon Young; Baik, Soon Koo; Cho, Mee Yon; Utsumi, Teruo; Satoh, Ayano; Ouyang, Xinsho; Chung, Chuhan; Iwakiri, Yasuko^*

来源：Hepatology, 2017, 65(5): 1720-1734.

DOI：10.1002/hep.29051

• ACTIVATED RECEPTOR-ALPHA
• FATTY LIVER
• MOLECULAR-MECHANISMS
• HEPATIC STEATOSIS
• MOUSE MODEL
• MICE
• MACROPHAGES
• DIFFERENTIATION
• PATHOGENESIS
• INFLAMMATION

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 = 20.48, 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. Conclusion: 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.

• 出版日期2017-5
• 单位中南大学