SAT-664 Transcriptional Coregulator GATA Zinc Finger Domain Containing 2A and Hepatic Lipid Homeostasis

Abstract Disclosure: A. Tsay: None. I. Su: None. K. Lam: None. J. Wang: None. The prevalence of Metabolic Dysfunction-Associate Steatotic Liver Disease (MASLD) has rapidly increased over the past two decades. Genetic factors play important roles in the development of MASLD. Genome-wide association studies (GWAS) have been valuable in identifying novel genes involved in developing various diseases, including MASLD. A single nucleotide polymorphism (SNP) in GATA zinc finger domain containing 2A (GATAD2A) gene, rs59148799, has been shown to be associated with MASLD in Japanese and Korean populations. However, the mechanism of how this GATAD2A SNP affects the development of MASLD is unknown. GATAD2A is a transcriptional coregulator and component of the nucleosome remodeling and deacetylase (NuRD) complex. The metabolic function of GATAD2A has not been identified. To learn whether hepatic GATAD2A affects lipid metabolism, we infected 8 weeks old male C57BL/6J mice with adeno-associated virus (AAV) expressing either scramble small hairpin RNA (shRNA, as a control) or shRNA targeting Gatad2a. We found that mice infected with AAV expressing Gatad2a shRNA had lower expression of Gatad2a in the liver but not in epididymal white adipose tissue and gastrocnemius muscle. Under chow diet feeding, hepatic Gatad2a knockdown resulted in lower fasting plasma and liver triglyceride levels. Looking into signaling pathways involved in lipid homeostasis regulation, we found that Gatad2a knockdown mice had significantly increased activity of hepatic AMP-activated protein kinase (AMPK) and decreased Acetyl-CoA Carboxylase (ACC1) activity, leading to inhibition of lipogenesis and promotion of fatty acid oxidation. Reducing Gatad2a expression in mouse AML12 hepatocytes also increased AMPK activity and reduced ACC1 activity, thus showing that this effect is cell autonomous. We performed liver RNA-sequencing and identified that N-myc downstream regulated gene 1 (Ndrg1) expression was reduced by Gatad2a knockdown. Ndrg1 expression was also reduced by Gatad2a knockdown in mouse AML12 hepatocytes, and, importantly, Ndrg1 depletion augmented AMPK activity. Moreover, overexpressing Gatad2a in mouse liver resulted in increased expression of Ndrg1 and liver TG levels. Chromatin immunoprecipitation (ChIP) revealed that Gatad2a was recruited to the promoter of mouse Ndrg1 gene. Based on these results, we propose that Gatad2a is a transcriptional coactivator promoting Ndrg1 transcription, which in turn suppresses AMPK to regulate lipid homeostasis. These results elucidate the novel function of GATAD2A in lipid metabolism and will provide important insights into the mechanism of MASLD development. Presentation: Saturday, July 12, 2025