RRC ID 81495
Author Gera J, Kumar D, Chauhan G, Choudhary A, Rani L, Mandal L, Mandal S.
Title High sugar diet-induced fatty acid oxidation potentiates cytokine-dependent cardiac ECM remodeling.
Journal J Cell Biol
Abstract Context-dependent physiological remodeling of the extracellular matrix (ECM) is essential for development and organ homeostasis. On the other hand, consumption of high-caloric diet leverages ECM remodeling to create pathological conditions that impede the functionality of different organs, including the heart. However, the mechanistic basis of high caloric diet-induced ECM remodeling has yet to be elucidated. Employing in vivo molecular genetic analyses in Drosophila, we demonstrate that high dietary sugar triggers ROS-independent activation of JNK signaling to promote fatty acid oxidation (FAO) in the pericardial cells (nephrocytes). An elevated level of FAO, in turn, induces histone acetylation-dependent transcriptional upregulation of the cytokine Unpaired 3 (Upd3). Release of pericardial Upd3 augments fat body-specific expression of the cardiac ECM protein Pericardin, leading to progressive cardiac fibrosis. Importantly, this pathway is quite distinct from the ROS-Ask1-JNK/p38 axis that regulates Upd3 expression under normal physiological conditions. Our results unravel an unknown physiological role of FAO in cytokine-dependent ECM remodeling, bearing implications in diabetic fibrosis.
Volume 223(9)
Published 2024-9-2
DOI 10.1083/jcb.202306087
PII 276823
PMID 38916917
PMC PMC11199913
MeSH Animals Cytokines / genetics Cytokines / metabolism Drosophila Proteins* / genetics Drosophila Proteins* / metabolism Drosophila melanogaster / metabolism Extracellular Matrix* / metabolism Fatty Acids* / metabolism Fibrosis / metabolism MAP Kinase Signaling System Myocardium / metabolism Myocardium / pathology Oxidation-Reduction* Pericardium / metabolism Pericardium / pathology Reactive Oxygen Species / metabolism Transcription Factors / genetics Transcription Factors / metabolism
Resource
Drosophila DGRC#116261 DGRC#116262