Abstract
Impairment of insulin clearance is being increasingly recognized as a critical step in the development of insulin resistance and metabolic disease. The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes insulin clearance. Null deletion or liver-specific inactivation of Ceacam1 in mice causes a defect in insulin clearance, insulin resistance, steatohepatitis, and visceral obesity. Immunohistological analysis revealed reduction of hepatic CEACAM1 in obese subjects with fatty liver disease. Thus, we aimed to determine whether this occurs at the hepatocyte level in response to systemic extrahepatic factors and whether this holds across species. Northern and Western blot analyses demonstrate that CEACAM1 mRNA and protein levels are reduced in liver tissues of obese individuals compared to their lean age-matched counterparts. Furthermore, Western analysis reveals a comparable reduction of CEACAM1 protein in primary hepatocytes derived from the same obese subjects. Similar to humans, Ceacam1 mRNA level, assessed by quantitative RT-PCR analysis, is significantly reduced in the livers of obese Zucker (fa/fa, ZDF) and Koletsky (f/f) rats relative to their age-matched lean counterparts. These studies demonstrate that the reduction of hepatic CEACAM1 in obesity occurs at the level of hepatocytes and identify the reduction of hepatic CEACAM1 as a common denominator of obesity across multiple species.
Highlights
The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is ubiquitously expressed [1]
Northern analysis indicates that CEACAM1 mRNA levels, normalized to GAPDH, are significantly lower in the liver of obese human subjects by comparison to those derived from their lean sex, race, and age-matched counterparts (Figure 1A)
This translates into reduced hepatic CEACAM1 protein levels in lysates derived from livers (Figure 1B) of obese human subjects, as assessed by Western blot analysis using Ib with antibodies against human CEACAM1 and GAPDH
Summary
The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is ubiquitously expressed [1]. Upon its phosphorylation by the insulin receptor tyrosine kinase in the hepatocyte [2], CEACAM1 promotes the uptake of insulin via its receptor to be degraded and cleared [3, 4]. Bolstering this function of CEACAM1, defective hepatic insulin clearance and subsequently, chronic hyperinsulinemia develops. Consistent with its positive effect on de novo lipogenesis [9], hyperinsulinemia causes hepatic lipid accumulation, as well as lipid redistribution to the white adipose depot for storage, resulting in elevated visceral obesity. Contributing to visceral obesity and increased total fat mass in Cc1−/− mice is leptin resistance, manifested by hyperphagia and reduced spontaneous physical activity [10]
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