PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy

Authors

• Xinyi Chen
• Andrea Ruiz-Velasco
• Zhiyong Zou
• Susanne S Hille
• Claire Ross
• Oveena Fonseka
• Sanskruti R Gare
• Nasser Hawimel O Alatawi
• Rida Raja
• Jiayan Zhang
• Namrita Kaur
• Xiangjun Zhao
• Henrietta Morrell-Davies
• Jessica M Miller
• Riham R E Abouleisa
• Qinghui Ou
• Derk Frank
• Martin K Rutter
• Christian Pinali
• Tao Wang
• Tamer M A Mohamed
• Oliver J Müller
• Wei Liu

Language

English

Publication Date

11-1-2024

Journal

Diabetes

DOI

10.2337/db24-0240

PMID

39137120

PMCID

PMC11493761

PubMedCentral® Posted Date

8-13-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating in heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate in cardiomyocytes, and seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated in obese human myocardium, and the murine hearts and cardiomyocytes upon diet- or fatty acid-induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible to the development of cardiac dysfunction upon diet stress, at least partially, because of increased deposition of toxic lipids within the myocardium. Mechanistically, PAK3 promoted the nuclear expression of sterol regulatory element binding protein 1c (SREBP1c) through activation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase β-1 (S6K1) pathway in cardiomyocytes, resulting in abnormal lipid genes profile, accumulation of excessive lipids, and oxidative stress. More importantly, PAK3 knockdown attenuated fatty acid-induced lipotoxicity and cell death in rat and human cardiomyocytes. More importantly, the S6K1 or SREBP1c inhibitor alleviated PAK3-triggered intracellular lipid overload and cardiac dysfunction under obese stress. Collectively, we have demonstrated that PAK3 impairs myocardial lipid homeostasis, while inhibition of cardiac lipotoxicity mitigates cardiac dysfunction. Our study provides a promising therapeutic strategy for ameliorating obesity cardiomyopathy.

Keywords

Sterol Regulatory Element Binding Protein 1, Animals, Humans, Obesity, Myocytes, Cardiac, Mice, Cardiomyopathies, Rats, p21-Activated Kinases, Oxidative Stress, Male, TOR Serine-Threonine Kinases, Myocardium, Ribosomal Protein S6 Kinases, 90-kDa, Lipid Metabolism, Signal Transduction

Published Open-Access

yes

Recommended Citation

Chen, Xinyi; Ruiz-Velasco, Andrea; Zou, Zhiyong; et al., "PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy" (2024). Faculty, Staff and Students Publications. 8617.
https://digitalcommons.library.tmc.edu/baylor_docs/8617