Protecting CEACAM1 Expression Prevents Diet-Induced Metabolic Dysfunction and Hepatic Fibrosis in Male Mice.

OBJECTIVE: High-fat diet represses Ceacam1 transcription via a PPARα-mediated mechanism to cause insulin resistance before inflammation develops. The current study investigated whether mutating PPRE-RXRα in Ceacam1 promoter prevents diet-induced metabolic abnormalities and hepatic fibrosis in male C57BL6/J mice. METHODS: A knock-in mouse line (KI) bearing mutation on PPRE-RXRα in Ceacam1 promoter was generated. Male mice were fed with regular chow, high-fat diet, or GAN diet for 1-4 months before insulin action was assessed in vivo by hyperinsulinemia-euglycemia clamp analysis and energy balance was analyzed by indirect calorimetry. H&E and Sirius Red staining were carried out to detect steatohepatitis and hepatic fibrosis, respectively. RESULTS: Feeding with high-fat or GAN diet for 1-4 months repressed hepatic CEACAM1 expression in wild-type but not KI mice. Mutating PPRE-RXRα prevented diet-induced impairment of insulin clearance to maintain normoinsulinemia and insulin sensitivity. High-fat diet failed to reduce energy expenditure and spontaneous locomotor activity in KI, as it did in wild-type mice. GAN feeding for 4 months caused mounting of a Th1-inflammatory response and hepatic fibrosis in wild-type but not KI mice. CONCLUSIONS: Blocking CEACAM1 repression while maintaining endogenous regulatory mechanisms and normal physiologic conditions sufficed to curb diet-induced metabolic dysregulation, steatosis, energy imbalance, and MASH progression.