Patients with
nonalcoholic fatty liver disease/
steatohepatitis (
NAFLD/NASH) commonly develop
atherosclerosis through a mechanism that is not well delineated. These diseases are associated with steatosis,
inflammation, oxidative stress, and
fibrosis. The role of
insulin resistance in their pathogenesis remains controversial.
Albumin (Alb)Cre+ Cc1flox ( fl ) /fl mice with the liver-specific null deletion of the
carcinoembryonic antigen-related cell adhesion molecule 1 (
Ceacam1; alias Cc1) gene display
hyperinsulinemia resulting from impaired
insulin clearance followed by hepatic
insulin resistance, elevated de novo lipogenesis, and ultimately
visceral obesity and systemic
insulin resistance. We therefore tested whether this mutation causes
NAFLD/NASH and
atherosclerosis. To this end, mice were propagated on a
low-density lipoprotein receptor (Ldlr) -/- background and at 4 months of age were fed a high-
cholesterol diet for 2 months. We then assessed the biochemical and histopathologic changes in liver and aortae. Ldlr-/-AlbCre+Cc1fl/fl mice developed chronic
hyperinsulinemia with proatherogenic
hypercholesterolemia, a robust proinflammatory state associated with
visceral obesity, elevated oxidative stress (reduced NO production), and an increase in plasma and tissue
endothelin-1 levels. In parallel, they developed NASH (
steatohepatitis, apoptosis, and
fibrosis) and
atherosclerotic plaque lesions. Mechanistically,
hyperinsulinemia caused down-regulation of the
insulin receptor followed by inactivation of the
insulin receptor substrate 1-protein
kinase B-endothelial
NO synthase pathway in aortae, lowering the NO level. This also limited
CEACAM1 phosphorylation and its sequestration of Shc-transforming
protein (Shc), activating the Shc-
mitogen-activated protein kinase-
nuclear factor kappa B pathway and stimulating
endothelin-1 production. Thus, in the presence of proatherogenic
dyslipidemia,
hyperinsulinemia and hepatic
insulin resistance driven by liver-specific deletion of
Ceacam1 caused metabolic and vascular alterations reminiscent of NASH and
atherosclerosis. Conclusion: Altered CEACAM1-dependent hepatic
insulin clearance pathways constitute a molecular link between NASH and
atherosclerosis.