Diminished CEACAM1 level plays a critical role in age-related hepatic fibrosis

Hepatic fibrosis increases with aging, but its physiological progression and underlying mechanisms remain poorly defined. Given that CEACAM1 repression causes metabolic dysfunction and liver injury, the current studies investigated whether it mediates age-related hepatic fibrosis.

The metabolic phenotype, histological, immunochemical and Western blot analyses were performed in male C57BL6/J wild-type and LCC1 mice with liver-specific CEACAM1 overexpression at 2-17 months of age.

Progression of metabolic dysfunction during physiological aging began with increased lipolysis-derived fatty acids, followed by hepatic insulin resistance with compensatory increase in insulin secretion and a decline in hepatic insulin clearance mediated initially by compromised CEACAM1 phosphorylation and then expression. Resultant hyperinsulinemia drove hepatic steatosis, followed by Th1 inflammatory response and subsequently, hepatic fibrosis at 17 months of age. These histological abnormalities regressed in LCC1 mice with protected hepatic CEACAM1 levels. Accordingly, LCC1 mice exhibited survival advantage.

This age-related mapping demonstrated that early metabolic alterations impaired insulin clearance with a progressive loss of CEACAM1. Resultant hyperinsulinemia drove hepatic steatosis followed by inflammation and ultimately, hepatic fibrosis in wild-type but not LCC1 mice. Together with survival benefit of LCC1, these observations propose that protecting hepatic CEACAM1 prevents age-related hepatic fibrosis and bestows longevity.