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Nature Metabolism Nov 2022Brown adipose tissue (BAT) activity contributes to cardiovascular health by its energy-dissipating capacity but how BAT modulates vascular function and atherosclerosis...
Brown adipose tissue (BAT) activity contributes to cardiovascular health by its energy-dissipating capacity but how BAT modulates vascular function and atherosclerosis through endocrine mechanisms remains poorly understood. Here we show that BAT-derived neuregulin-4 (Nrg4) ameliorates atherosclerosis in mice. BAT-specific Nrg4 deficiency accelerates vascular inflammation and adhesion responses, endothelial dysfunction and apoptosis and atherosclerosis in male mice. BAT-specific Nrg4 restoration alleviates vascular inflammation and adhesion responses, attenuates leukocyte homing and reduces endothelial injury and atherosclerosis in male mice. In endothelial cells, Nrg4 decreases apoptosis, inflammation and adhesion responses induced by oxidized low-density lipoprotein. Mechanistically, protein kinase B (Akt)-nuclear factor-κB signaling is involved in the beneficial effects of Nrg4 on the endothelium. Taken together, the results reveal Nrg4 as a potential cross-talk factor between BAT and arteries that may serve as a target for atherosclerosis.
Topics: Animals; Male; Mice; Adipose Tissue, Brown; Atherosclerosis; Endothelial Cells; Endothelium; Inflammation; Neuregulins
PubMed: 36400933
DOI: 10.1038/s42255-022-00671-0 -
Cell Metabolism Sep 2022The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that undergo pathophysiological reprogramming in disease states, such as...
The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that undergo pathophysiological reprogramming in disease states, such as non-alcoholic steatohepatitis (NASH). Patients with NASH are at an increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here, we show that diet-induced NASH is characterized by the induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic CD8+ T cells in the liver. The adipocyte-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbated the induction of tumor-prone liver immune microenvironment and NASH-related HCC, whereas transgenic NRG4 overexpression elicited protective effects in mice. In a therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potency in suppressing HCC and prolonged survival in the treated mice. These findings pave the way for therapeutic intervention of liver cancer by targeting the NRG4 hormonal checkpoint.
Topics: Animals; Carcinoma, Hepatocellular; Liver; Liver Neoplasms; Mammals; Mice; Neuregulins; Non-alcoholic Fatty Liver Disease; Tumor Microenvironment
PubMed: 35973424
DOI: 10.1016/j.cmet.2022.07.010 -
Cell Stem Cell Oct 2020Epidermal growth factor (EGF) maintains intestinal stem cell (ISC) proliferation and is a key component of organoid growth media yet is dispensable for intestinal...
Epidermal growth factor (EGF) maintains intestinal stem cell (ISC) proliferation and is a key component of organoid growth media yet is dispensable for intestinal homeostasis, suggesting roles for multiple EGF family ligands in ISC function. Here, we identified neuregulin 1 (NRG1) as a key EGF family ligand that drives tissue repair following injury. NRG1, but not EGF, is upregulated upon damage and is expressed in mesenchymal stromal cells, macrophages, and Paneth cells. NRG1 deletion reduces proliferation in intestinal crypts and compromises regeneration capacity. NRG1 robustly stimulates proliferation in crypts and induces budding in organoids, in part through elevated and sustained activation of mitogen-activated protein kinase (MAPK) and AKT. Consistently, NRG1 treatment induces a proliferative gene signature and promotes organoid formation from progenitor cells and enhances regeneration following injury. These data suggest mesenchymal-derived NRG1 is a potent mediator of tissue regeneration and may inform the development of therapies for enhancing intestinal repair after injury.
Topics: Cell Proliferation; Epithelium; Intestines; Neuregulin-1; Paneth Cells
PubMed: 32693086
DOI: 10.1016/j.stem.2020.06.021 -
Genes & Development Sep 2023Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial...
Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass and synergized with KRAS inhibitors in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.
Topics: Humans; Animals; Mice; Proto-Oncogene Proteins p21(ras); Cell Proliferation; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Neuregulin-1
PubMed: 37775182
DOI: 10.1101/gad.351037.123 -
Stem Cell Reports Apr 2020Ovarian cancer (OC) represents the most dismal gynecological cancer. Pathobiology is poorly understood, mainly due to lack of appropriate study models. Organoids,...
Ovarian cancer (OC) represents the most dismal gynecological cancer. Pathobiology is poorly understood, mainly due to lack of appropriate study models. Organoids, defined as self-developing three-dimensional in vitro reconstructions of tissues, provide powerful tools to model human diseases. Here, we established organoid cultures from patient-derived OC, in particular from the most prevalent high-grade serous OC (HGSOC). Testing multiple culture medium components identified neuregulin-1 (NRG1) as key factor in maximizing OC organoid development and growth, although overall derivation efficiency remained moderate (36% for HGSOC patients, 44% for all patients together). Established organoid lines showed patient tumor-dependent morphology and disease characteristics, and recapitulated the parent tumor's marker expression and mutational landscape. Moreover, the organoids displayed tumor-specific sensitivity to clinical HGSOC chemotherapeutic drugs. Patient-derived OC organoids provide powerful tools for the study of the cancer's pathobiology (such as importance of the NRG1/ERBB pathway) as well as advanced preclinical tools for (personalized) drug screening and discovery.
Topics: Antineoplastic Agents; Female; Humans; Models, Biological; Neuregulin-1; Organ Culture Techniques; Organoids; Ovarian Neoplasms
PubMed: 32243841
DOI: 10.1016/j.stemcr.2020.03.004 -
Nature Medicine Dec 2014Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat...
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 we 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. These results establish Nrg4 as a brown fat-enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).
Topics: 3T3-L1 Cells; Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; Animals; Fatty Liver; HEK293 Cells; Humans; Insulin Resistance; Lipogenesis; Liver; Liver X Receptors; Mice; Neuregulins; Obesity; Orphan Nuclear Receptors; RNA, Messenger; Receptor, ErbB-3; Receptor, ErbB-4; Sterol Regulatory Element Binding Protein 1
PubMed: 25401691
DOI: 10.1038/nm.3713 -
Journal of Ovarian Research Jul 2022Granulosa cells (GCs) are multilayered somatic cells within the follicle that provide physical support and microenvironment for the developing oocyte. In recent years,...
BACKGROUND
Granulosa cells (GCs) are multilayered somatic cells within the follicle that provide physical support and microenvironment for the developing oocyte. In recent years, the role of Neuregulin-1 (NRG1), a member of the EGF-like factor family, has received considerable attention due to its neurodevelopmental and cardiac function. However, the exact physiological role of NRG1 in GC is mainly unknown. In order to confirm that NRG1 plays a regulatory role in rat GC functions, endogenous NRG1-knockdown studies were carried out in GCs using RNA interference methodology.
RESULTS
Knockdown of NRG1 in GCs resulted in the enhanced expression and secretion of the cytokines and chemokines. In addition, the phosphorylation of PI3K/Akt/ERK1/2 was significantly low in GCs under these experimental conditions. Moreover, in vitro experimental studies suggest that tumor necrosis factor-α (TNFα) treatment causes the physical destruction of GCs by activating caspase-3/7 activity. In contrast, exogenous NRG1 co-treatment of GCs delayed the onset of TNFα-induced apoptosis and inhibited the activation of caspase-3/7 activity. Furthermore, current experimental studies suggest that gonadotropins promote differential expression of NRG1 and ErbB3 receptors in GCs of the antral follicle. Interestingly, NRG1 and ErbB3 were intensely co-localized in the mural and cumulus GCs and cumulus-oocyte complex of pre-ovulatory follicles in the estrus stage.
CONCLUSIONS
The present studies suggest that gonadotropins-dependent NRG1-signaling in GCs may require the balance of the cytokines and chemokines expression and secretion, ultimately which may be supporting the follicular maturation and oocyte competence for ovulation and preventing follicular atresia.
Topics: Animals; Caspase 3; Chemokines; Cytokines; Female; Follicular Atresia; Gonadotropins; Granulosa Cells; Neuregulin-1; Phosphatidylinositol 3-Kinases; Rats; Tumor Necrosis Factor-alpha
PubMed: 35883098
DOI: 10.1186/s13048-022-01021-0 -
American Journal of Medical Genetics.... Mar 2018Neuregulins, a four-member family of epidermal growth factor-like signaling molecules, have been studied for over two decades. They were first implicated in... (Review)
Review
Neuregulins, a four-member family of epidermal growth factor-like signaling molecules, have been studied for over two decades. They were first implicated in schizophrenia in 2002 with the detection of linkage and association at the NRG1 locus followed after a few years by NRG3. However, the associations with disease have not been very consistently observed. In contrast, association of NGR3 variants with disease presentation, specifically the presence of delusions, has been more consistent. This appears to be mediated by quantitative changes in the alternative splicing of the gene, which has also been consistently observed. Additional diseases and phenotypes, psychiatric or not, have also been connected with NRG3. These results demonstrate two important aspects of behavioral genetics research. The first is that if we only consider simple risk and fail to examine the details of each patient's individual phenotype, we will miss important insights on the disease biology. This is an important aspect of the goals of precision medicine. The second is that the functional consequences of variants are often more complex than simple alterations in levels of transcription of a particular gene, including, among others, regulation of alternative splicing. To accurately model and understand the biological consequences of phenotype-associated genetic variants, we need to study the biological consequences of each specific variant. Simply studying the consequences of a null allele of the orthologous gene in a model system, runs the risk of missing the many nuances of hypomorphic and/or gain of function variants in the genome of interest.
Topics: Alternative Splicing; Genetic Linkage; Genotype; Humans; Neuregulin-1; Neuregulins; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Schizophrenia
PubMed: 28556469
DOI: 10.1002/ajmg.b.32552 -
BMC Medicine Feb 2024Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field... (Review)
Review
BACKGROUND
Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions.
MAIN BODY
Approximately 0.15-0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS.
CONCLUSION
Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neoplasms; Neuregulin-1; Receptor, ErbB-4; Signal Transduction
PubMed: 38369520
DOI: 10.1186/s12916-024-03293-3 -
EMBO Reports May 2023The growth factor Neuregulin-1 (NRG-1) regulates myocardial growth and is currently under clinical investigation as a treatment for heart failure. Here, we demonstrate...
The growth factor Neuregulin-1 (NRG-1) regulates myocardial growth and is currently under clinical investigation as a treatment for heart failure. Here, we demonstrate in several in vitro and in vivo models that STAT5b mediates NRG-1/EBBB4-stimulated cardiomyocyte growth. Genetic and chemical disruption of the NRG-1/ERBB4 pathway reduces STAT5b activation and transcription of STAT5b target genes Igf1, Myc, and Cdkn1a in murine cardiomyocytes. Loss of Stat5b also ablates NRG-1-induced cardiomyocyte hypertrophy. Dynamin-2 is shown to control the cell surface localization of ERBB4 and chemical inhibition of Dynamin-2 downregulates STAT5b activation and cardiomyocyte hypertrophy. In zebrafish embryos, Stat5 is activated during NRG-1-induced hyperplastic myocardial growth, and chemical inhibition of the Nrg-1/Erbb4 pathway or Dynamin-2 leads to loss of myocardial growth and Stat5 activation. Moreover, CRISPR/Cas9-mediated knockdown of stat5b results in reduced myocardial growth and cardiac function. Finally, the NRG-1/ERBB4/STAT5b signaling pathway is differentially regulated at mRNA and protein levels in the myocardium of patients with pathological cardiac hypertrophy as compared to control human subjects, consistent with a role of the NRG-1/ERBB4/STAT5b pathway in myocardial growth.
Topics: Mice; Humans; Animals; Dynamin II; Neuregulin-1; STAT5 Transcription Factor; Zebrafish; Receptor, ErbB-4; Hypertrophy
PubMed: 37009825
DOI: 10.15252/embr.202256689