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Role of Na/K-ATPase α1 caveolin-binding motif in adipogenesis.
Huang, Minqi; Wang, Xiaoliang; Chen, Yiliang; Pessoa, Marco T; Terrell, Kayleigh C; Zhang, Jue; Tian, Jiang; Xie, Zijian; Pierre, Sandrine V; Cai, Liquan.
Afiliação
  • Huang M; Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States.
  • Wang X; Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States.
  • Chen Y; Versiti Blood Research Institute, Milwaukee, West Virginia, United States.
  • Pessoa MT; Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
  • Terrell KC; Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States.
  • Zhang J; Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States.
  • Tian J; Versiti Blood Research Institute, Milwaukee, West Virginia, United States.
  • Xie Z; Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
  • Pierre SV; Marshall Institute for Interdisciplinary Research, Marshall University, Huntington, West Virginia, United States.
  • Cai L; Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States.
Am J Physiol Cell Physiol ; 327(1): C48-C64, 2024 Jul 01.
Article em En | MEDLINE | ID: mdl-38708522
ABSTRACT
Deficiencies in mice and in humans have brought to the fore the importance of the caveolar network in key aspects of adipocyte biology. The conserved N-terminal caveolin-binding motif (CBM) of the ubiquitous Na/K-ATPase (NKA) α1 isoform, which allows NKA/caveolin-1 (Cav1) interaction, influences NKA signaling and caveolar distribution. It has been shown to be critical for animal development and ontogenesis, as well as lineage-specific differentiation of human induced pluripotent stem cells (hiPSCs). However, its role in postnatal adipogenesis has not been fully examined. Using a genetic approach to alter CBM in hiPSC-derived adipocytes (iAdi-mCBM) and in mice (mCBM), we investigated the regulatory function of NKA CBM signaling in adipogenesis. Seahorse XF cell metabolism analyses revealed impaired glycolysis and decreased ATP synthesis-coupled respiration in iAdi-mCBM. These metabolic dysfunctions were accompanied by evidence of extensive remodeling of the extracellular matrix (ECM), including increased collagen staining, overexpression of ECM marker genes, and heightened TGF-ß signaling uncovered by RNAseq analysis. Rescue of mCBM by lentiviral delivery of WT NKA α1 or treatment of mCBM hiPSCs with the TGF-ß inhibitor SB431542 normalized ECM, suggesting that NKA CBM signaling integrity is required for adequate control of TGF-ß signaling and ECM stiffness during adipogenesis. The physiological impact was revealed in mCBM male mice with reduced fat mass accompanied by histological and transcriptional evidence of elevated adipose fibrosis and decreased adipocyte size. Based on these findings, we propose that the genetic alteration of the NKA/Cav1 regulatory path uncovered in human iAdi leads to lipodystrophy in mice.NEW & NOTEWORTHY A Na/K-ATPase α1 caveolin-binding motif regulates adipogenesis. Mutation of this binding motif in the mouse leads to reduced fat with increased extracellular matrix production and inflammation. RNA-seq analysis and pharmacological interventions in human iPSC-derived adipocytes revealed that TGF-ß signal, rather than Na/K-ATPase-mediated ion transport, is a key mediator of NKA regulation of adipogenesis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adipócitos / ATPase Trocadora de Sódio-Potássio / Caveolina 1 / Adipogenia / Células-Tronco Pluripotentes Induzidas Limite: Animals / Humans / Male Idioma: En Revista: Am J Physiol Cell Physiol Assunto da revista: FISIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Adipócitos / ATPase Trocadora de Sódio-Potássio / Caveolina 1 / Adipogenia / Células-Tronco Pluripotentes Induzidas Limite: Animals / Humans / Male Idioma: En Revista: Am J Physiol Cell Physiol Assunto da revista: FISIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos