Metabolic-Associated Steatotic Liver Disease and FGF21 Dysregulation in Seipin-Deficient and BSCL2-Associated Celia’s Encephalopathy Murine Models

Seipin, a protein encoded by the <i>BSCL2</i> gene, plays a crucial role in lipid metabolism, and some pathogenic biallelic variants cause lipodystrophy and associated metabolic disorders. This study investigates liver pathology and dysregulation of the <i>FGF21</i> signalling pathway in two mouse models: <i>Bscl2</i>^-/- (knock-out) and <i>Bscl2</i>^Celia/Celia (knock-in). We evaluated liver histopathology using H&E and Oil red O staining, assessed hepatic triglyceride levels via enzymatic assays, and analyzed gene expression of key <i>FGF21</i>-related components (<i>Fgf21</i>, <i>Ppargc1a</i>, <i>Fgfr1</i>, and <i>Klb</i>) using quantitative real-time PCR. The liver histology was scored using the NAFLD activity score (NAS) system. Both models exhibited hepatic steatosis and inflammatory features. The <i>Bscl2</i>^-/- mice showed more pronounced liver damage, including ballooning degeneration and fibrosis. Gene expression analysis revealed a significant increase in <i>Fgf21</i> in both models, suggesting an adaptive response to liver injury. Notably, <i>Fgfr1</i> and <i>Ppargc1a</i> expression was moderately elevated in severe neurologically affected mice showing less hepatic involvement, suggesting a potential adaptive or protective association of these genes with reduced steatosis. Seipin deficiency leads to metabolic-associated steatotic liver disease and dysregulated <i>FGF21</i> signalling. These findings provide insight into the pathophysiological mechanisms of lipodystrophy and liver disease and suggest that the <i>FGF21</i> pathway could be a therapeutic target for treating seipin-related metabolic disorders.