Altered drug metabolism and increased susceptibility to fatty liver disease in an inducible liver-specific mouse model of myotonic dystrophy

Abstract

Myotonic Dystrophy type 1 (DM1), a prevalent muscular dystrophy affecting 1 in 2800 individuals, is associated with a toxic (CTG)n repeat expansion in the DMPK gene. While DM1 affects multiple systems, recent studies highlight its link to liver pathology, glucose intolerance, and drug sensitivity. Our study focused on liver implications by creating a hepatocyte-specific DM1 mouse model. Expression of toxic RNA in hepatocytes sequestered muscleblind-like (MBNL) proteins, impacting hepatocellular activity. DM1-induced liver alterations included morphological changes, inflammation, necrosis, and fatty accumulation. Impaired drug metabolism and clearance were evident in DM1 mice and increased susceptibility to diet-induced fatty liver disease. Notably, alternative splicing of acetyl-CoA carboxylase 1 induced excessive lipid accumulation in DM1 livers, exacerbated by high-fat, high-sugar diets. These findings unveil disruptions in hepatic functions, predisposing DM1 livers to injury, fatty liver disease, and compromised drug clearance. Understanding these mechanisms is crucial for addressing the complex health challenges in DM1 patients and optimizing treatment strategies.