Loss of Hepatic CEACAM1: A Unifying Mechanism Linking Insulin Resistance to Obesity and Non-Alcoholic Fatty Liver Disease

Heinrich, Garrett; Ghadieh, Hilda E.; Ghanem, Simona S.; Muturi, Harrison T.; Rezaei, Khadijeh; Al-Share, Qusai Y.; Bowman, Thomas A.; Zhang, Deqiang; Garofalo, Robert S.; Yin, Lei; Najjar, Sonia M.

doi:10.3389/fendo.2017.00008

Cited by 32 publications

(38 citation statements)

References 73 publications

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“…Consistent with the predominant expression of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the liver [5], we have shown that CEACAM1 provides a post-receptor mechanistic underpinning of how impaired insulin clearance causes chronic hyperinsulinaemia [6–8]. Upon its phosphorylation by the insulin receptor [9], CEACAM1, a plasma membrane glycoprotein, increases the rate of receptor-mediated insulin uptake into the hepatocyte and its targeting to the degradation pathways by taking part in the insulin receptor endocytosis complex [10].…”

Section: Introductionmentioning

confidence: 74%

Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

et al. 2017

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Aims/hypothesis The carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes insulin clearance. Mice with global null mutation (Cc1−/−) or with liver-specific inactivation (L-SACC1) of Cc1 (also known as Ceacam1) gene display hyperinsulinaemia resulting from impaired insulin clearance, insulin resistance, steatohepatitis and obesity. Because increased lipolysis contributes to the metabolic phenotype caused by transgenic inactivation of CEACAM1 in the liver, we aimed to further investigate the primary role of hepatic CEACAM1-dependent insulin clearance in insulin and lipid homeostasis. To this end, we examined whether transgenic reconstitution of CEACAM1 in the liver of global Cc1−/− mutant mice reverses their abnormal metabolic phenotype. Methods Insulin response was assessed by hyperinsulinaemic–euglycaemic clamp analysis and energy balance was analysed by indirect calorimetry. Mice were overnight-fasted and refed for 7 h to assess fatty acid synthase activity in the liver and the hypothalamus in response to insulin release during refeeding. Results Liver-based rescuing of CEACAM1 restored insulin clearance, plasma insulin level, insulin sensitivity and steatohepatitis caused by global deletion of Cc1. It also reversed the gain in body weight and total fat mass observed with Cc1 deletion, in parallel to normalising energy balance. Mechanistically, reversal of hyperphagia appeared to result from reducing fatty acid synthase activity and restoring insulin signalling in the hypothalamus. Conclusions/interpretation Despite the potential confounding effects of deleting Cc1 from extrahepatic tissues, liver-based rescuing of CEACAM1 resulted in full normalisation of the metabolic phenotype, underscoring the key role that CEACAM1-dependent hepatic insulin clearance pathways play in regulating systemic insulin sensitivity, lipid homeostasis and energy balance.

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Section: Introductionmentioning

confidence: 74%

Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

et al. 2017

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“…As a result of the specific insulin-degrading enzyme, insulin degradation begins right before the acidification. In addition, enzyme CEACAM1 promotes insulin clearance by enhancing the rate of uptake of the insulin-receptor complex (29). Dissociated insulin is degraded in endosomes, translocated to cytosol and degraded there, or delivered to other subcellular compartments, such as peroxisomes (28).…”

Section: Discussionmentioning

confidence: 99%

Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women

2017

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African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20–25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes.

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“…29 Recently, enzyme CEACAM1 has been shown to promote the rate of uptake of the insulin-receptor complex. 30 IDE and/or CEACAM1 expression might be specifically reduced, inactivated or genetically altered in AAs, and possibly in HAs, because of genetic inheritance. Inactivation of CEACAM1 has been related to hyperinsulinaemia, insulin resistance, dyslipidaemia and visceral adiposity in transgenic mice 31 through downregulation of insulin receptors and increased hepatic lipogenesis.…”

Section: Discussionmentioning

confidence: 99%

Dissection of hepatic versus extra‐hepatic insulin clearance: Ethnic differences in childhood

Piccinini

Polidori

Gower

et al. 2018

Diabetes Obesity Metabolism

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Loss of Hepatic CEACAM1: A Unifying Mechanism Linking Insulin Resistance to Obesity and Non-Alcoholic Fatty Liver Disease

Cited by 32 publications

References 73 publications

Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

Hepatic but Not Extrahepatic Insulin Clearance Is Lower in African American Than in European American Women

Dissection of hepatic versus extra‐hepatic insulin clearance: Ethnic differences in childhood

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