RNA-Seq of livers of Gata4LKO and control mouse on LXR agonist GW3965

GATA4 is a transcription factor known for its crucial role in the development of many tissues, including liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, including assay for transposase-accessible chromatin with sequencing (ATAC-Seq), we identified GATA4 as a transcriptional regulator of metabolism in liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of genes involved in cholesterol export and triglyceride hydrolysis was downregulated and the expression of those involved in lipid uptake were upregulated in Gata4LKO liver, We further demonstrate that GATA4 collaborates with LXR liver. GATA4 shares a number of binding sites and direct transcriptional targets with LXRs, and loss of GATA4 impairs the hepatic transcriptional response to LXR agonist. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis. Overall design: RNA-Seq of frozen liver tissue from GW3965 vs DMSO treated GATA4 Liver KO (Gata4 floxed/floxed; AAV8-Tbg-Cre) or Control (Gata4 floxed/floxed; AAV8-Empty) mice. Nine-week-old mice on Gata4LKO and control mice, 1 week after AAV injection, were gavaged with 40 mg/kg GW3965 prepared in canola oil (Collins et al. 2002) at 17 h, and then 8 h before before sacrifice. Mice were 4 h fasted at the time of killing. Dimethylsulfoxide in canola oil was used as vehicle control.