NRG4

Case study 1: Guo-Xiao Wang, 2014

Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here the researchers show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner.

Fig1. Secretion of Nrg4 into culture media. Shown are immunoblots of total lysates from ErbB4-Min6 cells treated with DMEM or concentrated conditioned media (CM) from HEK293 (top) or BAC (bottom) expressing vector (Vec) or Nrg4.

Fig2. SEAP-Nrg4Ex binding to liver sections in the presence of excess recombinant GST or GST-Nrg4Ex.

Case study 2: Steven J McElroy, 2014

Necrotizing enterocolitis (NEC) affects up to 10% of premature infants, has a mortality of 30%, and can leave surviving patients with significant morbidity. Neuregulin-4 (NRG4) is an ErbB4-specific ligand that promotes epithelial cell survival. Thus, this pathway could be protective in diseases such as NEC, in which epithelial cell death is a major pathologic feature.

NRG4 was used i) in the newborn rat formula feeding/hypoxia model; ii) in a recently developed model in which 14- to 16-day-old mice are injected with dithizone to induce Paneth cell loss, followed by Klebsiella pneumoniae infection to induce intestinal injury; and iii) in bacterially infected IEC-6 cells in vitro. NRG4 reduced NEC incidence and severity in the formula feed/hypoxia rat model. It also reduced Paneth cell ablation-induced NEC and prevented dithizone-induced Paneth cell loss in mice. In vitro, cultured ErbB4(-/-) ileal epithelial enteroids had reduced Paneth cell markers and were highly sensitive to inflammatory cytokines. Furthermore, NRG4 blocked, through a Src-dependent pathway, Cronobacter muytjensii-induced IEC-6 cell apoptosis.

Fig3. leums from 14-day-old mice subjected to DK NEC, with or without NRG4, underwent staining by Alcian blue/periodic acid–Schiff (AB/PAS) and immunohistochemical analysis for lysozyme to identify Paneth cells.

Fig4. Western blot analysis of the ileal mucosal scrapings from 14-day-old mice injected with varying doses of NRG4 for phospho-ErbB4 and phospho-Src.

Fig1. Regular ERBB4 membrane signaling and resulting metabolism-related processes. (Maria Vulf, 2023)

Fig2. Model of Nrg4 as a brown fat-enriched secreted protein that preserves metabolic homeostasis in diet-induced obesity. (Guo-Xiao Wang, 2014)

NRG4 involved in several pathways and played different roles in them. We selected most pathways NRG4 participated on our site, such as ARMS-mediated activation, Adaptive Immune System, Axon guidance, which may be useful for your reference. Also, other proteins which involved in the same pathway with NRG4 were listed below. Creative BioMart supplied nearly all the proteins listed, you can search them on our site.

NRG4 has several biochemical functions, for example, growth factor activity, protein binding, receptor binding. Some of the functions are cooperated with other proteins, some of the functions could acted by NRG4 itself. We selected most functions NRG4 had, and list some proteins which have the same functions with NRG4. You can find most of the proteins on our site.

NRG4 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with NRG4 here. Most of them are supplied by our site. Hope this information will be useful for your research of NRG4.

FATE1; CREB3