PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity CardiomyopathyShort Title: PAK3 provokes cardiac lipotoxicity

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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, due to 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 beta-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. Article Highlights: · Obesity increases the risk of cardiac dysfunction; however, effective treatments remain absent. Here, we investigate an underlying mechanism of obesity cardiomyopathy. · We found that PAK3 expression is increased in the myocardium of obese human and mouse models. PAK3 upregulation mediates the nuclear SREBP1c via activation of mTOR and S6K1, resulting in myocardial lipid overload. · Inhibition of either PAK3 and S6K1 pathway or SREBP1c prevents lipotoxicity and exerts beneficial effects on cardiomyocyte survival. · Pharmacological inhibition of S6K1 and SREBP1c in vivo proved effective in modulating cardiac lipid homeostasis and delaying the progression of obesity cardiomyopathy.

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