TCF7l2 Regulates Fatty Acid Chain Elongase HACD3 during Lipid-Induced Stress

The transcriptional regulation of metabolic genes is crucial for maintaining metabolic homeostasis under cellular stress conditions. Transcription factor 7-like 2 (TCF7l2 or TCF4) is associated with type 2 diabetes (T2D) and functions as a transcription factor for various gluconeogenic genes. T2D often coexists with metabolic dysfunction-associated steatotic liver disease (MASLD) due to common underlying mechanisms and shared risk factors such as insulin resistance and obesity. This study demonstrates the transcriptional regulation of one of the important fatty acid chain elongases implicated in T2D, HACD3 (encoded by <i>PTPLAD1</i> gene), under palmitic acid (PA)-induced stress conditions. We observed that TCF7l2 is associated with histone H3K4me3-binder protein TCF19 and is corecruited to the promoter of <i>PTPLAD1</i>. Upon PA treatment, the TCF19-TCF7l2 complex dissociates from the lipid chain elongase gene due to the reduced level of H3K4me3 enrichment, leading to <i>PTPLAD1</i> activation. Remarkably, gene expression analysis from the PA-injected mice and NAFLD patients indicates an anticorrelation whereby reduced TCF7l2 expression enhances HACD3-mediated chain elongation and triglyceride production, thereby promoting the development of MASLD. Our findings delineate that the epigenetic mechanism of activation of lipid chain elongase genes mediated by TCF7l2 in concert with TCF19 has important implications in metabolic disorders.