Dataset Information

Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1.

ABSTRACT:

Objective

NAFLD is a complex disease marked by cellular abnormalities leading to NASH. NAFLD patients manifest low hepatic levels of CEACAM1, a promoter of insulin clearance. Consistently, Cc1^-/- null mice displayed spontaneous hyperinsulinemia/insulin resistance and steatohepatitis. Liver-specific reconstitution of Ceacam1 reversed these metabolic anomalies in 8-month-old Cc1^-/-xliver+ mice fed a regular chow diet. The current study examined whether it would also reverse progressive hepatic fibrosis in mice fed a high-fat (HF) diet.

Methods

3-Month-old mice were fed a high-fat diet for 3-5 months, and metabolic and histopathological analysis were conducted to evaluate their NASH phenotype.

Results

Reconstituting CEACAM1 to Cc1^-/- livers curbed diet-induced liver dysfunction and NASH, including macrovesicular steatosis, lobular inflammation, apoptosis, oxidative stress, and chicken-wire bridging fibrosis. Persistence of hepatic fibrosis in HF-fed Cc1^-/- treated with nicotinic acid demonstrated a limited role for lipolysis and adipokine release in hepatic fibrosis caused by Ceacam1 deletion.

Conclusions

Restored metabolic and histopathological phenotype of HF-fed Cc1^{-/-xliver+xliver+} assigned a critical role for hepatic CEACAM1 in preventing NAFLD/NASH including progressive hepatic fibrosis.

SUBMITTER: Helal RA

PROVIDER: S-EPMC8286970 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1.

Helal Raghd Abu RA Russo Lucia L Ghadieh Hilda E HE Muturi Harrison T HT Asalla Suman S Lee Abraham D AD Gatto-Weis Cara C Najjar Sonia M SM

Metabolism: clinical and experimental 20210528

<h4>Objective</h4>NAFLD is a complex disease marked by cellular abnormalities leading to NASH. NAFLD patients manifest low hepatic levels of CEACAM1, a promoter of insulin clearance. Consistently, Cc1<sup>-/-</sup> null mice displayed spontaneous hyperinsulinemia/insulin resistance and steatohepatitis. Liver-specific reconstitution of Ceacam1 reversed these metabolic anomalies in 8-month-old Cc1<sup>-/-xliver+</sup> mice fed a regular chow diet. The current study examined whether it would also r ...[more]

PMID: 34058224

Similar Datasets

Project description: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.

Dataset Information

Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1.

Objective

Methods

Results

Conclusions

Publications

Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1.

Similar Datasets

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