Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance

Al-Share, Qusai Y.; DeAngelis, Anthony M.; Lester, Sumona Ghosh; Bowman, Thomas A.; Ramakrishnan, S; Abdallah, Simon L.; Russo, Lucía; Patel, Payal R.; Kaw, Meenakshi; Raphael, Christian K.; Kim, Andrea Jung; Heinrich, Garrett; Lee, Abraham D.; Kim, Jason K.; Kulkarni, Rohit; Philbrick, William M.; Najjar, Sonia M.

doi:10.2337/db14-1772

Cited by 47 publications

(116 citation statements)

References 51 publications

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“…Normal acute-phase insulin release to glucose and intact -cell function support the observation that chronic hyperinsulinemia is mainly driven by impaired insulin clearance in Cc1 / mutants (15). Studies in mice (17), dogs (18), and humans (19) demonstrated that defective hepatic insulin clearance is involved in diet-induced insulin resistance. Providing a Western-style diet caused rapid hepatic insulin resistance in healthy young South Asian men but not Caucasians, in association with altered insulin clearance in the Asian group (19).…”

Section: Ex Vivo Palmitate Oxidationmentioning

confidence: 71%

“…Providing a Western-style diet caused rapid hepatic insulin resistance in healthy young South Asian men but not Caucasians, in association with altered insulin clearance in the Asian group (19). We have shown that high fat (HF) reduced hepatic CEACAM1 level by >60% and impaired insulin clearance in WT mice within 3 weeks to introduce metabolic abnormalities that were prevented by forced transgenic fat-inducible CEACAM1 overexpression in liver (17). The clinical implication of our studies is underscored by the observed low hepatic CEACAM1 level in obese, insulinresistant subjects with fatty liver disease (20).…”

Section: Ex Vivo Palmitate Oxidationmentioning

confidence: 94%

“…Mice were individually caged for 5 days (CLAMS system, Columbus Instrument), and their spontaneous physical activity was determined on the X-(locomotor), Y-(ambulatory), and Z-(standing) axes (17). Oxygen consumption (VO 2 ), CO 2 production (VCO 2 ), and heat production were sampled every 20 min and normalized to lean mass.…”

Section: Indirect Calorimetry Analysismentioning

confidence: 99%

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Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis

Russo

Ghadieh

Ghanem

et al. 2016

Journal of Lipid Research

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Supplementary key words carcinoembryonic antigen-related cell adhesion molecule 1 • insulin resistance • nicotinic acid • lipolysis • insulin clearanceCirculating insulin levels, in part determined by hepatic insulin clearance, regulate insulin action (1-3). Insulin clearance, which occurs mostly in liver and to a lower extent in kidney, but not in skeletal muscle or white adipose tissue (WAT), plays a pivotal role in promoting insulin sensitivity (4). If impaired, it contributes to mounting hyperinsulinemia in obese humans (5, 6), thus constituting a risk factor for metabolic syndrome (7,8).Our studies on the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a transmembrane glycoprotein that is highly expressed in liver and kidney, but not WAT or skeletal muscle (9), support these findings. Upon its phosphorylation by the insulin receptor, CEACAM1 promotes insulin clearance by upregulating receptor-mediated insulin uptake into clathrin-coated pits and degradation in hepatocytes (10). Moreover, it mediates a downregulatory effect on mouse fatty acid synthase Abstract Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance and mediating suppression of fatty acid synthase activity. Feeding C57BL/6J male mice with a high-fat (HF) diet for 3-4 weeks triggered a >60% decrease in hepatic CEACAM1 levels to subsequently impair insulin clearance and cause systemic insulin resistance and hepatic steatosis. This study aimed at investigating whether lipolysis drives reduction in hepatic CEACAM1 and whether this constitutes a key mechanism leading to diet-induced metabolic abnormalities. Blocking lipolysis with a daily intraperitoneal injection of nicotinic acid in the last two days of a 30-day HF feeding regimen demonstrated that white adipose tissue (WAT)-derived fatty acids repressed hepatic CEACAM1-dependent regulation of insulin and lipid metabolism in 3-month-old male C57BL/6J mice. Adenoviralmediated CEACAM1 redelivery countered the adverse metabolic effect of the HF diet on insulin resistance, hepatic steatosis, visceral obesity, and energy expenditure. It also reversed the effect of HF diet on inflammation and fibrosis in WAT and liver. This assigns a causative role for lipolysis-driven decrease in hepatic CEACAM1 level and its regulation of insulin and lipid metabolism in sustaining systemic insulin resistance, hepatic steatosis, and other abnormalities associated with excessive energy supply.-Russo, L., H. E. Ghadieh, S. S. Ghanem, Q. Y. Al-Share, Z. N. Smiley, C. Gatto-Weis, E. L. Esakov, M. F. McInerney, G. Heinrich, X. Tong, L. Yin, and S. M. Najjar. Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocytehepatocyte axis.

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Section: Ex Vivo Palmitate Oxidationmentioning

confidence: 71%

Section: Ex Vivo Palmitate Oxidationmentioning

confidence: 94%

Section: Indirect Calorimetry Analysismentioning

confidence: 99%

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Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis

Russo

Ghadieh

Ghanem

et al. 2016

Journal of Lipid Research

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“…Of note, CEACAM2 is expressed in the kidney but not liver (4,29). Whether it plays a role in renal insulin clearance is not known but, given that insulin clearance occurs mostly in the liver where CEACAM1 expression dominates, insulin clearance is not expected to be directly affected by Ceacam2 deletion, and elevation in insulin clearance in Cc2 Ϫ/Ϫ mice would be mediated by CEACAM1 phosphorylation in response to insulin in liver (8 -10) as well as kidney (36).…”

Section: Discussionmentioning

confidence: 99%

Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2)

Ghanem¹,

Heinrich²,

Lester³

et al. 2016

Journal of Biological Chemistry

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“…[38][39][40] Moreover, correlations of NASH-associated CpG sites with mRNA expression of CEACAM1, SH3BP4 (encoding transferrin receptor-trafficking protein), and NAT2 also support a role for our findings relating differential DNA methylation in NASH with impaired insulin signaling/action. [41][42][43][44][45][46][47] The mechanisms that could alter DNA methylation in the insulin-resistant liver remain to be elucidated. However, these differences in methylation may be due to altered levels of enzymes responsible for adding or removing methyl groups to the genome, such as DNMTs.…”

Section: Discussionmentioning

confidence: 99%

Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

et al. 2017

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Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 § 7.7 years, BMI: 43 § 5.7 kg/m 2 , type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q < 0.001), independently of T2D, age, sex, and BMI. Focusing on the top-ranking 30 and another 37 CpG sites mapped to genes enriched in pathways of metabolism (q D 0.0036) and cancer (q D 0.0001) all together, 59 NASH-associated CpG sites correlated with fasting insulin levels independently of age, fasting glucose, or T2D. From these, we identified 30 correlations between DNA methylation and mRNA expression, for example LDHB (r D ¡0.45, P D 0.003). We demonstrated that NASH, more than simple steatosis, associates with differential DNA methylation in the human liver. These epigenetic alterations in NASH are linked with insulin metabolism.

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Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance

Cited by 47 publications

References 51 publications

Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis

Role for hepatic CEACAM1 in regulating fatty acid metabolism along the adipocyte-hepatocyte axis

Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2)

Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

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