Corticosterone induces fatty liver syndrome in chickens via glucocorticoid receptor and inhibition of mitochondrial supercomplex formation

Stress is a primary contributor to fatty liver syndrome (FLS) in chickens. Mitochondrial functionality is pivotal in FLS progression, with diminished supercomplex (SC) formation disrupting electron transport and escalating reactive oxygen species (ROS) production. However, the impact of stress on mitochondrial SC in chicken FLS remains elusive. This study used corticosterone (CORT) to model chronic stress and examined its consequences on mitochondrial performance and SC configuration in both in vivo and in vitro FLS models. Notably, the CORT-treated hepatocytes exhibited elevated triglyceride content (<i>P</i> < 0.05), accompanied by increased mitochondrial ROS (<i>P</i> < 0.01). Moreover, CORT-exposed broilers displayed reduced body weight (<i>P</i> < 0.05) alongside heightened liver-to-body weight ratio (<i>P</i> < 0.01), indicative of liver steatosis with increased triglyceride levels in both liver and plasma (<i>P</i> < 0.01). Mitochondrial alterations in reduced ATP content (<i>P</i> < 0.05). Gene expression analysis revealed enrichment in the mitochondrial respiratory chain pathway, with downregulated mRNA expression of complex I-associated SC assembly factors NADH: ubiquinone oxidoreductase complex assembly factor 5 (<i>NDUFAF5</i>), NADH: ubiquinone oxidoreductase complex assembly factor, and translocase of inner mitochondrial membrane domain containing 1 (<i>P</i> < 0.05). Meanwhile, the glucocorticoid receptor (GR) protein level and its specific binding to the <i>NDUFAF5</i> gene promoter were reduced in the CORT group (<i>P</i> < 0.01 and <i>P</i> < 0.05, respectively), accompanied by a decrease in NDUFAF5 protein expression in liver, primary hepatocytes, and AML12 cells (<i>P</i> < 0.05). GR knockdown in AML12 cells reduced NDUFAF5 protein expression (<i>P</i> < 0.05). Thus, these findings imply that GR-mediated transcriptional regulation of complex I assembly factor NDUFAF5 may influence SC assembly, shedding light on stress-induced FLS mechanisms in broilers.<b>NEW & NOTEWORTHY</b> This study reveals the pivotal role of GR-mediated transcriptional regulation in stress-induced FLS in chickens. Chronic stress modeled with CORT disrupted mitochondrial SC assembly, impairing electron transport, elevated ROS production, and liver steatosis. Notably, the downregulation of complex I assembly factors (<i>NDUFAF5</i>, <i>NDUFAF7</i>, and <i>TIMMDC1</i>) and reduced GR binding to <i>NDUFAF5</i> were key mechanisms. These findings provide new insights into stress-driven mitochondrial dysfunction in broiler FLS.