Protecting
CEACAM1
Expression Prevents Diet‐Induced Metabolic Dysfunction and Hepatic Fibrosis in Male Mice
Raziyeh Abdolahipour, Saja S. Khuder, William M. Philbrick, Agnes O. Portuphy, Getachew D. Belew, Hatem G. Fallouh, Harrison T. Muturi, Boyeon Kim, Jason K. Kim, Sonia M. Najjar ABSTRACT
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.