Loss of Early Growth Response Protein 1 in the Liver Leads to Hepatic Lipid Accumulation Driven by an Imbalance Between Fatty Acid β-Oxidation and Oxidative Phosphorylation

Background and Aims: Metabolic-associated fatty liver disease is a worldwide health problem characterized by increased hepatic lipid accumulation, leading to conditions like steatohepatitis, cirrhosis, and liver cancer. Early growth response protein 1 (EGR1) gene encodes an immediate early transcription factor that regulates a wide variety of cellular processes in response to stress and injury. Whole-body Egr1 knockout studies suggest a role for EGR1 in metabolism, affecting insulin sensitivity, energy homeostasis, cholesterol biosynthesis, and circadian rhythm. However, its direct role in hepatic lipid metabolism remains unclear. This study aimed to investigate the function of EGR1 in the adult liver. Methods: Hepatocyte-specific EGR1-deficient male mice were generated using CRISPR/Cas9. Mice were maintained under chow-fed conditions or challenged with a high-fat diet (HFD). Hepatic lipid levels, zonation, and gene expression were analyzed. Oxygen consumption was measured in mouse and human hepatocytes. Results: After a HFD challenge, hepatic EGR1-deficient mice showed a significant increase in hepatic triglyceride levels. Transcriptome analysis revealed an upregulation of genes related to fatty acid oxidation and downregulation of mitochondrial respiration genes in livers of both chow and HFD hepatic EGR1-deficient mice. Functional analysis showed reduced maximum oxygen consumption in EGR1-deficient mouse and human hepatocytes. Fasting-induced hepatic lipid accumulation indeed indicated reduced fatty acid oxidation efficiency upon ablation of EGR1. Conclusion: Hepatic EGR1 deficiency significantly alters lipid metabolism and mitochondrial function, indicating a role of EGR1 in regulating the balance between mitochondrial fatty acid β-oxidation and respiration in the liver.