An endoplasmic reticulum protein, Nogo‐B, facilitates alcoholic liver disease through regulation of kupffer cell polarization

Abstract

Background Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Since 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). Methods 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 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. Results 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). Further, Nogo-B positive Kupffer cells correlated with M1 activation (iNOS) (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 to 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 for 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.

O-GlcNAc transferase suppresses necroptosis and liver fibrosis

“…As O-GlcNAcylation is a highly dynamic PTM, acute or chronic changes in O-GlcNAc signaling may lead to different outcomes by modulating different substrates (22). It is also noteworthy that, in our mouse model of ethanol diet-induced liver injury, hepatocyte injury and inflammation were evident, while no obvious fibrosis was developed before the mice were sacrificed (34). The levels of liver O-GlcNAcylation were already decreased significantly in these mice.…”

“…We also examined the changes in O-GlcNAc levels in a mouse model of ethanol-induced liver injury. Mice were fed with a Lieber-DeCarli liquid diet to induce alcoholic steatosis and liver inflammation (34). Decreased liver O-GlcNAc levels were seen in mice fed with the ethanol diet as compared with the control group, which could be explained by the reduced expression of OGT in ethanol-fed mice ( Figure 1C).…”

Rosiglitazone alleviates intrahepatic cholestasis induced by α‐naphthylisothiocyanate in mice: The role of circulating 15‐deoxy‐Δ12,14‐PGJ2 and Nogo

“…Increased circulating Nogo‐B has been reported in several different disease states (Gao et al, ; Men et al, ; Sutendra et al, ), whereas Nogo‐B deficiency is known to ameliorate liver fibrosis and portal hypertension by inactivating the TGFβ signalling pathway (Tashiro, Satoh, Utsumi, Chung, & Iwakiri, ; Zhang et al, ) and to reduce alcoholic liver disease by regulating Kupffer cell polarization (Park et al, ). In this study, we found that Nogo‐B might facilitate intrahepatic cholestasis.…”

O-GlcNAc transferase suppresses necroptosis and liver fibrosis

“…Mice were fasted for 6 hr before sacrifice and tissues were collected for protein and RNA extraction and histology analysis. Ethanol-induced liver injury was induced as described before (35). Briefly, mice were fed with a Lieber-DeCarli liquid diet (F1258SP, BioServ, Flemington, NJ) or a control diet (F1259SP, BioServ) that has a matched calorie with ethanol diet for 6 weeks.…”