Modulation of Nuclear Receptor 4A1 Expression Improves Insulin Secretion in a Mouse Model of Chronic Pancreatitis.

Autor:	Sheethal G; From the Asian Healthcare Foundation, AIG Hospitals., Verma A; CSIR-CCMB, Centre for Cellular and Molecular Biology, Hyderabad, India., Mall R; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN., Parsa KV; Centre for Innovation in Molecular and Pharmaceutical Sciences, Dr Reddy's Institute of Life Sciences., Tokala RK; From the Asian Healthcare Foundation, AIG Hospitals., Bynigeri R; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN., Pondugala PK; From the Asian Healthcare Foundation, AIG Hospitals., Vemula K; From the Asian Healthcare Foundation, AIG Hospitals., Sai Latha S; Centre for Innovation in Molecular and Pharmaceutical Sciences, Dr Reddy's Institute of Life Sciences., Sowpati DT; CSIR-CCMB, Centre for Cellular and Molecular Biology, Hyderabad, India., Singh SS; Department of Biochemistry, Osmania University., Rao GV; Asian Institute of Gastroenterology (AIG Hospitals), Hyderabad, India., Talukdar R; Asian Institute of Gastroenterology (AIG Hospitals), Hyderabad, India., Kanneganti TD; Department of Immunology, St Jude Children's Research Hospital, Memphis, TN., Reddy DN; Asian Institute of Gastroenterology (AIG Hospitals), Hyderabad, India., Sasikala M; From the Asian Healthcare Foundation, AIG Hospitals.
Jazyk:	angličtina
Zdroj:	Pancreas [Pancreas] 2024 Oct 01; Vol. 53 (9), pp. e760-e773. Date of Electronic Publication: 2024 May 04.
DOI:	10.1097/MPA.0000000000002370
Abstrakt:	Objectives: Diabetes secondary to chronic pancreatitis (CP) presents clinical challenges due to lack of understanding on factor(s) triggering insulin secretory defects. Therefore, we aimed to delineate the molecular mechanism of β-cell dysfunction in CP. Materials and Methods: Transcriptomic analysis was conducted to identify endocrine-specific receptor expression in mice and human CP on microarray. The identified receptor (NR4A1) was overexpressed in MIN6 cells using PEI linear transfection. RNA-Seq analysis of NR4A1-overexpressed (OE) MIN6 cells on NovaSeq6000 identified aberrant metabolic pathways. Upstream trigger for NR4A1OE was studied by InBio Discover and cytokine exposure, whereas downstream effect was examined by Fura2 AM-based fluorimetric and imaging studies. Mice with CP were treated with IFN-γ-neutralizing monoclonal antibodies to assess NR4A1 expression and insulin secretion. Results: Increased expression of NR4A1 associated with decreased insulin secretion in islets (humans: controls 9 ± 0.2, CP 3.7 ± 0.2, mice: controls 8.5 ± 0.2, CP 2.1 ± 0.1 μg/L). NR4A1OE in MIN6 cells (13.2 ± 0.1) showed reduction in insulin secretion (13 ± 5 to 0.2 ± 0.1 μg/mg protein per minute, P = 0.001) and downregulation of calcium and cAMP signaling pathways. IFN-γ was identified as upstream signal for NR4A1OE in MIN6. Mice treated with IFN-γ-neutralizing antibodies showed decreased NR4A1 expression 3.4 ± 0.11-fold ( P = 0.03), showed improved insulin secretion (4.4 ± 0.2-fold, P = 0.01), and associated with increased Ca 2+ levels (2.39 ± 0.06-fold, P = 0.009). Conclusions: Modulating NR4A1 expression can be a promising therapeutic strategy to improve insulin secretion in CP. (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
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