Myocardial lipid accumulation causes cardiac inflammation and dysfunction through Nr4a1 in a sex-dependent manner

Cardiac-specific knockout of ABHD5 (ABHD5 cKO), a lipid droplet-associated protein, leads to defects in lipid utilization characterized by massive lipid accumulation, fibrosis, and reduced ejection fraction. In these mice, Nr4a1 is upregulated via the HDAC4-MEF2 axis, leading to the activation of the hexosamine biosynthesis pathway, resulting in cardiac dysfunction. Here, we show that the cardiac-specific knockout of Nr4a1 in ABHD5 cKO (cDKO) partially rescues the cardiac phenotype of ABHD5 cKO. However, we detected improved cardiac function and less fibrosis without change in total lipid accumulation only in female but not male cDKO mice. This was accompanied by profound sex-specific transcriptome profile differences in female cDKO mice. Although no major metabolic alterations were observed, pro-inflammatory cytokine markers (TNF alpha, IL-1 beta, and IL-6) were significantly downregulated in cDKO compared to ABHD5 cKO mice, pointing to a potential causative link underlying meta-inflammation. Such as, this study provides evidence that Nr4a1 mediates pro-inflammatory responses that trigger cardiac dysfunction. Our data reveal, that not lipid accumulation per se induces cardiac dysfunction, but that the pro-inflammatory state is caused by associated processes. In this regard, inhibition of Nr4a1 could be a new targeted principle to counteract cardiac dysfunction and meta-inflammation related to lipid accumulation in the heart.