PPARα (Peroxisome Proliferator-activated Receptor α) Activation Reduces Hepatic CEACAM1 Protein Expression to Regulate Fatty Acid Oxidation during Fasting-refeeding Transition

Ramakrishnan, S; Khuder, Saja S.; Al-Share, Qusai Y.; Russo, Lucía; Abdallah, Simon L.; Patel, Payal R.; Heinrich, Garrett; Muturi, Harrison T.; Mopidevi, Brahmaraju; Oyarce, Ana María; Shah, Yatrik M.; Sánchez, Edwin R.; Najjar, Sonia M.

doi:10.1074/jbc.m116.714014

Cited by 30 publications

(54 citation statements)

References 38 publications

(44 reference statements)

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“…2C-ii). Consistent with our previous observations (12), the downregulatory effect of FA appears to be mediated by Ppar activation, as demonstrated by the ability of FA (0.1 mM) to reduce the transcriptional activity of Ceacam1 WT promoter (1,100), but not of the construct harboring a mutation of the sole active Ppar response element (PPRE/RXR) located between nucleotides -557 and -543 (Fig. 2D).…”

Section: Na Induces Macrophage Inflammation In Wat Of Hf-fed Micesupporting

confidence: 74%

“…We have reported that CEACAM1 downregulates Fasn activity to prevent steatosis in liver (11). We have also shown that PPAR reduces Ceacam1 transcription to regulate fatty acid -oxidation during the fasting-refeeding transition (12) and in response to fenofibrate treatment (44). Because fatty acids are the endogenous ligands of PPAR (45), it is conceivable that adipose tissue-derived fatty acids reduce CEACAM1 levels by a PPAR-mediated mechanism as shown by failure of fatty acids to downregulate the transcriptional activity of a promoter construct bearing a mutation on the active PPRE/RXR site in Ceacam1 promoter, as they did to the WT promoter.…”

Section: Adenoviral-redelivery Of Ceacam1 Rescues Energy Expenditure mentioning

confidence: 93%

“…This positions CEACAM1 to contribute to the regulation of fatty acid oxidation until glycogen repletion is complete (12). Mice with null deletion of Ceacam1 (Cc1 / ) or with liver-specific inactivation of CEACAM1 develop hyperinsulinemia, caused by impaired insulin clearance, followed by insulin resistance, hepatic steatosis, and visceral obesity (13)(14)(15)(16).…”

Section: Ex Vivo Palmitate Oxidationmentioning

confidence: 99%

“…Then 1 ml of the homogenate was added to a sealed beaker containing 1 ml of solution A and left at 30°C for 45 min. Solution A: 0.2 mM of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitate (0.5 mCi/ml) (American Radiolabeled Chemicals Inc.) and 2 mM ATP in incubation buffer (100 mM sucrose, 10 mM Tris-HCl, 5 mM potassium phosphate, 80 mM KCl, 1 mM MgCl 2 , 2 mM l-carnitine, 0.1 mM malic acid, 0.05 mM CoA, 1mM dithiothreitol, 0.2 mM EDTA, and 0.5% BSA, pH 7.4). Benzothonium hydroxide (Sigma-Aldrich) was added to a basket attached to the sealed beaker and the reaction was terminated with perchloric acid to recover the radioactive acid soluble metabolites (29).…”

Section: Ex Vivo Palmitate Oxidationmentioning

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: Na Induces Macrophage Inflammation In Wat Of Hf-fed Micesupporting

confidence: 74%

Section: Adenoviral-redelivery Of Ceacam1 Rescues Energy Expenditure mentioning

confidence: 93%

Section: Ex Vivo Palmitate Oxidationmentioning

confidence: 99%

Section: Ex Vivo Palmitate Oxidationmentioning

confidence: 99%

See 2 more Smart Citations

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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“…In the current study, the most striking findings are that diet cholesterol increases body weight without any change in brain weight. It modifies plasma (19) protein expression as a cholesterol homeostasis-related protein (11) and BACE1 as a protein related to APP processing (12) in the hippocampi of Wistar rats, while also inducing irregularities in memory recall. Based on our data, body weight gain in the test group (hypercholestrolemic) rats was significantly higher than weight gain in the control rats fed with a normal diet.…”

Section: Discussionmentioning

confidence: 99%

High Cholesterol Diet Increases Expression of Cholesterol 24-Hydroxylase and BACE1 in Rat Hippocampi: Implications for the Effect of Diet Cholesterol on Memory

Nikasa¹,

Karimi²,

Rajavand³

et al. 2016

Iran Red Crescent Med J

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Background: Abnormal cholesterol homeostasis is associated with the pathogenesis of neurodegenerative disease and cognitive impairment. Objectives: Our objective was to evaluate changes in the expression of proteins related to cognition and cholesterol homeostasis in the hippocampi of rats as well as behavioral modifications following the administration of a cholesterol-rich diet. Methods: In this experimental study, lasting 16 weeks, 20 male Wistar rats (aged 8 weeks) were randomly divided into two groups. One group was fed with a normal diet (ND; n = 10) and the second with a high cholesterol diet (HD; n = 10). The expression of the cognition-related proteins N-methyl-D-aspartate receptor (NMDAR) and beta-secretase 1 (BACE1) and cholesterol 24-hydroxylase (CYP46A1), the key cholesterol hemostasis protein, were determined by an immunoblotting assay in the hippocampus homogenate. The Morris water maze (MWM) test was used to examine cognitive performance. Plasma lipidic parameters, including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG), as well as brain TC were measured by colorimetric assay. Results: After a high cholesterol diet had been administered for a period of 16 weeks, a significant increase in TC, LDL-C and TG was observed in the HD group in comparison with the ND group (P < 0.05). Neither the mean of brain wet weight nor brain TC showed significant change in the HD versus the ND group (P = 0.114, P = 0.84, respectively). Despite this fixity, differences in the expression of BACE1 and CYP46A1 were significant (P < 0.05) between the two groups, with high levels of BACE1 and CYP46A1 in the HD group compared with the ND group. These biochemical changes were associated with a significant decrease in the time traveled on a platform quadrant in the HD versus the ND group (P < 0.05) during a spatial memory probe test administered at the same time. Conclusions:The findings show that irregularities in cognitive performance as a result of a high cholesterol diet can be partially mediated by distortion in brain cholesterol homeostasis and processing of the amyloid precursor protein (APP).

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Exenatide induces carcinoembryonic antigen‐related cell adhesion molecule 1 expression to prevent hepatic steatosis

Ghadieh

Muturi

Russo

et al. 2017

Hepatology Communications

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Exenatide, a glucagon‐like peptide‐1 receptor agonist, induces insulin secretion. Its role in insulin clearance has not been adequately examined. Carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance to maintain insulin sensitivity. Feeding C57BL/6J mice a high‐fat diet down‐regulates hepatic Ceacam1 transcription to cause hyperinsulinemia, insulin resistance, and hepatic steatosis, as in Ceacam1 null mice (Cc1 –/–). Thus, we tested whether exenatide regulates Ceacam1 expression in high‐fat diet‐fed mice and whether this contributes to its insulin sensitizing effect. Exenatide (100 nM) induced the transcriptional activity of wild‐type Ceacam1 promoter but not the constructs harboring block mutations of peroxisome proliferator‐activated receptor response element and retinoid X receptor alpha, individually or collectively, in HepG2 human hepatoma cells. Chromatin immunoprecipitation analysis demonstrated binding of peroxisome proliferator‐activated receptor gamma to Ceacam1 promoter in response to rosiglitazone and exenatide. Consistently, exenatide induced Ceacam1 messenger RNA expression within 12 hours in the absence but not in the presence of the glucagon‐like peptide‐1 receptor antagonist exendin 9‐39. Exenatide (20 ng/g body weight once daily intraperitoneal injection in the last 30 days of feeding) restored hepatic Ceacam1 expression and insulin clearance to curb diet‐induced metabolic abnormalities and steatohepatitis in wild‐type but not Cc1 –/– mice fed a high‐fat diet for 2 months. Conclusion: Exenatide promotes insulin clearance in parallel with insulin secretion to prevent chronic hyperinsulinemia and the resulting hepatic steatosis, and this contributes to its insulin sensitizing effect. Our data further highlight the relevance of physiologic insulin metabolism in maintaining insulin sensitivity and normal lipid metabolism. (Hepatology Communications 2018;2:35–47)

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PPARα (Peroxisome Proliferator-activated Receptor α) Activation Reduces Hepatic CEACAM1 Protein Expression to Regulate Fatty Acid Oxidation during Fasting-refeeding Transition

Cited by 30 publications

References 38 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

High Cholesterol Diet Increases Expression of Cholesterol 24-Hydroxylase and BACE1 in Rat Hippocampi: Implications for the Effect of Diet Cholesterol on Memory

Exenatide induces carcinoembryonic antigen‐related cell adhesion molecule 1 expression to prevent hepatic steatosis

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