ACSL6 alleviates myocardial hypertrophy by ameliorating cardiac lipid synthesis and mitochondrial function.

AIMS: Myocardial hypertrophy is a key pathological basis for heart failure, closely related to disturbances in cardiac lipid metabolism and impaired mitochondrial function. Long-chain acyl-CoA synthetase 6 (ACSL6) is a pivotal enzyme in fatty acid metabolism, but its role in myocardial hypertrophy remains unclear. This study aims to investigate the role of ACSL6 in myocardial hypertrophy and its potential mechanisms.

MATERIALS AND

METHODS

Mouse models of myocardial hypertrophy induced by isoproterenol (ISO) and neonatal mouse cardiomyocyte (NMCM) hypertrophy models intervened by angiotensin II (Ang II) were established. Using lentivirus-mediated ACSL6 overexpression, co-immunoprecipitation, mass spectrometry, lipidomics, transmission electron microscopy, and molecular biology techniques, the functions and mechanisms of ACSL6 were explored.

KEY FINDINGS: ACSL6 was downregulated in ISO-induced myocardial hypertrophic mouse tissues and Ang II-treated NMCMs, with expression decreasing as Ang II intervention duration increased. ACSL6 overexpression significantly alleviated myocardial hypertrophy, improved cardiac function, and mitigated cell damage and hypertrophic marker upregulation. Additionally, ACSL6 overexpression inhibited myocardial lipid synthesis and accumulation, ameliorated lipid metabolic disorder, and enhanced mitochondrial function in ISO-induced mice. Mechanistically, KRT17 bound to ACSL6, competing with E3 ubiquitin ligase MIB1, protecting ACSL6 from ubiquitination and degradation. KRT17 knockdown reversed the protective effects of ACSL6 overexpression, exacerbating lipid accumulation and mitochondrial dysfunction.

SIGNIFICANCE: ACSL6 alleviated myocardial hypertrophy by ameliorating cardiac lipid synthesis and mitochondrial function. KRT17 stabilized ACSL6 expression by inhibiting its ubiquitination and degradation, mediating ACSL6's protective effects. Targeting the KRT17-ACSL6 axis emerged as a promising strategy for treating myocardial hypertrophy.