Abstract Body (Do not enter title and authors here): Background: Lipid metabolism plays a crucial role in in cardiovascular disease pathophysiology. Lipin1 is a key regulator of lipid metabolism. In the nucleus, lipin1 acts as a transcriptional coactivator, interacting with PGC1α and PPARα. In the cytoplasm, it functions as a phosphatidate phosphatase, converting phosphatidic acid to diacylglycerol. Low expression of Lipin1 has been implicated in the severity of cardiac dysfunction in mice.

Hypothesis: We hypothesized that Lipin1 protects against myocardial ischemic injury by regulating lipid homeostasis in cardiomyocytes, thereby attenuating adverse remodeling, inflammation, and oxidative stress following infarction.

Aims: To investigate the role of Lipin1 in cardiac remodeling after myocardial infarction (MI), revealing its impact on lipid metabolism and molecular pathway associated with cardiac dysfunction.

Methods: Cardiomyocyte-specific Lipin1 knockout (cKO) and overexpression (cOE) mice were used. Eight to ten-week-old male mice were subjected to MI by coronary artery ligation. One week after MI, cardiac lipid droplet (LD) density, levels of triacylglycerol and free fatty acids were quantified. Four weeks after MI, echocardiographic assessments, heart weight (HW)/ body weight (BW) ratio were recorded. Histological and gene expression analyses were performed to evaluate cardiac fibrosis, inflammation, oxidative stress, and fatty acid metabolism.

Results: Before MI surgery, there were no differences in HW/BW ratio, left ventricular end-diastolic diameter (LVDd) or LV fractional area change (LVFAC) among cKO/ cOE mice and their littermate controls. After MI, cKO mice exhibited significant cardiac dysfunction with enlarged LVDd, reduced LVFAC and increased HW/BW ratio. These changes were accompanied by increased cardiac fibrosis, inflammation, and reactive oxygen species compared with their controls. Conversely, cOE mice showed improved LVFAC, reduced cardiac fibrosis, inflammation, and oxidative stress. Notably, after MI surgery, cKO mice showed a reduction in cardiac LDs with decreased levels of triacylglycerol and free fatty acids compared to the littermate controls. In contrast, cOE mice displayed increased cardiac LDs and upregulated expression of fatty acid metabolism–related genes after MI.

Conclusion: These findings demonstrate that Lipin1 protects ischemic cardiomyocytes by regulating lipid metabolism, highlighting its potential as a therapeutic target for MI.