2. Academic Validation
  3. HNF4α ubiquitination mediated by Peli1 impairs FAO and accelerates pressure overload-induced myocardial hypertrophy

HNF4α ubiquitination mediated by Peli1 impairs FAO and accelerates pressure overload-induced myocardial hypertrophy

  • Cell Death Dis. 2024 Feb 12;15(2):135. doi: 10.1038/s41419-024-06470-7.
Yuxing Hou # 1,  Pengxi Shi # 1,  Haiyang Du 1,  Chenghao Zhu 1,  Chao Tang 1 2,  Linli Que 1,  Guoqing Zhu 3,  Li Liu 4,  Qi Chen 1,  Chuanfu Li 5,  Guoqiang Shao 6,  Yuehua Li 7,  Jiantao Li 8
Affiliations

Affiliations

  • 1 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, 211166, China.
  • 2 Department of Pathology and Pathophysiology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, 211166, China.
  • 4 Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 5 Department of Surgery, East Tennessee State University, Campus Box 70575, Johnson City, TN, 37614-0575, USA.
  • 6 Department of nuclear medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210029, China. guoqiangshao@163.com.
  • 7 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, 211166, China. yhli@njmu.edu.cn.
  • 8 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, School of Basic Medical Science, Nanjing Medical University, Nanjing, 211166, China. ljt@njmu.edu.cn.
  • # Contributed equally.
PMID: 38346961 DOI: 10.1038/s41419-024-06470-7
Abstract

Impaired fatty acid oxidation (FAO) is a prominent feature of metabolic remodeling observed in pathological myocardial hypertrophy. Hepatocyte nuclear factor 4alpha (HNF4α) is closely associated with FAO in both cellular processes and disease conditions. Pellino 1 (Peli1), an E3 ligase containing a RING-like domain, plays a crucial role in catalyzing polyubiquitination of various substrates. In this study, we aimed to investigate the involvement of HNF4α and its ubiquitination, facilitated by Peli1, in FAO during pressure overload-induced cardiac hypertrophy. Peli1 systemic knockout mice (Peli1KO) display improved myocardial hypertrophy and cardiac function following transverse aortic constriction (TAC). RNA-seq analysis revealed that changes in gene expression related to lipid metabolism caused by TAC were reversed in Peli1KO mice. Importantly, both HNF4α and its downstream genes involved in FAO showed a significant increase in Peli1KO mice. We further used the antagonist BI6015 to inhibit HNF4α and delivered rAAV9-HNF4α to elevate myocardial HNF4α level, and confirmed that HNF4α inhibits the development of cardiac hypertrophy after TAC and is essential for the enhancement of FAO mediated by Peli1 knockout. In vitro experiments using BODIPY incorporation and FAO stress assay demonstrated that HNF4α enhances FAO in cardiomyocytes stimulated with angiotension II (Ang II), while Peli1 suppresses the effect of HNF4α. Mechanistically, immunoprecipitation and mass spectrometry analyses confirmed that Peli1 binds to HNF4α via its RING-like domain and promotes HNF4α ubiquitination at residues K307 and K309. These findings shed LIGHT on the underlying mechanisms contributing to impaired FAO and offer valuable insights into a promising therapeutic strategy for addressing pathological cardiac hypertrophy.

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