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- An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization.
An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization.
Citation | “An Endoplasmic Reticulum Protein, Nogo-B, Facilitates Alcoholic Liver Disease Through Regulation Of Kupffer Cell Polarization.”. Hepatology (Baltimore, Md.), pp. 1720-1734. . |
Center | Yale University |
Author | Jin-Kyu Park, Mingjie Shao, Moon Young Kim, Soon Koo Baik, Mee Yon Cho, Teruo Utsumi, Ayano Satoh, Xinsho Ouyang, Chuhan Chung, Yasuko Iwakiri |
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. 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. (Hepatology 2017;65:1720-1734). |
Year of Publication |
2017
|
Journal |
Hepatology (Baltimore, Md.)
|
Volume |
65
|
Issue |
5
|
Number of Pages |
1720-1734
|
Date Published |
12/2017
|
ISSN Number |
1527-3350
|
DOI |
10.1002/hep.29051
|
Alternate Journal |
Hepatology
|
PMID |
28090670
|
PMCID |
PMC5397326
|
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