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ABSTRACT: Liver-specific inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 causes hyperinsulinemia and insulin resistance, which result from impaired insulin clearance, in liver-specific S503A carcinoembryonic antigen-related cell adhesion molecule 1 mutant mice (L-SACC1). These mice also develop steatosis. Because hepatic fat accumulation precedes hepatitis, lipid peroxidation, and apoptosis in the pathogenesis of nonalcoholic steatohepatitis (NASH), we investigated whether a high-fat diet, by causing inflammation, is sufficient to induce hepatitis and other features of NASH in L-SACC1 mice.
L-SACC1 and wild-type mice were placed on a high-fat diet for 3 months, then several biochemical and histologic analyses were performed to investigate the NASH phenotype.
A high-fat diet caused hepatic macrosteatosis and hepatitis, characterized by increased hepatic tumor necrosis factor alpha levels and activation of the NF-kappaB pathway in L-SACC1 but not in wild-type mice. The high-fat diet also induced necrosis and apoptosis in the livers of the L-SACC1 mice. Insulin resistance in L-SACC1 fed a high-fat diet increased the hepatic procollagen protein level, suggesting a role in the development of fibrosis.
A high-fat diet induces key features of human NASH in insulin-resistant L-SACC1 mice, validating this model as a tool to study the molecular mechanisms of NASH.
Gastroenterology 08/2008; 135(6):2084-95. · 11.68 Impact Factor
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Arnt Erik Tjønna,
Sang Jun Lee,
Øivind Rognmo,
Tomas O Stølen,
Anja Bye,
Per Magnus Haram,
Jan Pål Loennechen, Qusai Y Al-Share,
Eirik Skogvoll,
Stig A Slørdahl,
Ole J Kemi,
Sonia M Najjar,
Ulrik Wisløff
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ABSTRACT: Individuals with the metabolic syndrome are 3 times more likely to die of heart disease than healthy counterparts. Exercise training reduces several of the symptoms of the syndrome, but the exercise intensity that yields the maximal beneficial adaptations is in dispute. We compared moderate and high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with the metabolic syndrome.
Thirty-two metabolic syndrome patients (age, 52.3+/-3.7 years; maximal oxygen uptake [o(2)max], 34 mL x kg(-1) x min(-1)) were randomized to equal volumes of either moderate continuous moderate exercise (CME; 70% of highest measured heart rate [Hfmax]) or aerobic interval training (AIT; 90% of Hfmax) 3 times a week for 16 weeks or to a control group. o(2)max increased more after AIT than CME (35% versus 16%; P<0.01) and was associated with removal of more risk factors that constitute the metabolic syndrome (number of factors: AIT, 5.9 before versus 4.0 after; P<0.01; CME, 5.7 before versus 5.0 after; group difference, P<0.05). AIT was superior to CME in enhancing endothelial function (9% versus 5%; P<0.001), insulin signaling in fat and skeletal muscle, skeletal muscle biogenesis, and excitation-contraction coupling and in reducing blood glucose and lipogenesis in adipose tissue. The 2 exercise programs were equally effective at lowering mean arterial blood pressure and reducing body weight (-2.3 and -3.6 kg in AIT and CME, respectively) and fat.
Exercise intensity was an important factor for improving aerobic capacity and reversing the risk factors of the metabolic syndrome. These findings may have important implications for exercise training in rehabilitation programs and future studies.
Circulation 08/2008; 118(4):346-54. · 14.74 Impact Factor
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Sonia M Najjar,
Yan Yang,
Mats A Fernström,
Sang-Jun Lee,
Anthony M Deangelis,
George A Abou Rjaily, Qusai Y Al-Share,
Tong Dai,
Tiffany A Miller,
Shobha Ratnam,
Randall J Ruch,
Stuart Smith,
Sue-Hwa Lin,
Nicole Beauchemin,
Ana Maria Oyarce
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ABSTRACT: Insulin is viewed as a positive regulator of fatty acid synthesis by increasing fatty acid synthase (FAS) mRNA transcription. We uncover a new mechanism by which insulin acutely reduces hepatic FAS activity by inducing phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and its interaction with FAS. Ceacam1 null mice (Cc1(-/-)) show loss of insulin's ability to acutely decrease hepatic FAS activity. Moreover, adenoviral delivery of wild-type, but not the phosphorylation-defective Ceacam1 mutant, restores the acute effect of insulin on FAS activity in Cc1(-/-) primary hepatocytes. Failure of insulin to acutely reduce hepatic FAS activity in hyperinsulinemic mice, including L-SACC1 transgenics with liver inactivation of CEACAM1, and Ob/Ob obese mice, suggests that the acute effect of insulin on FAS activity depends on the prior insulinemic state. We propose that this mechanism acts to reduce hepatic lipogenesis incurred by insulin pulses during refeeding.
Cell Metabolism 08/2005; 2(1):43-53. · 13.67 Impact Factor
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ABSTRACT: Phosphorylation of the cell adhesion protein CEACAM1 increases insulin sensitivity and decreases insulin-dependent mitogenesis in vivo. Here we show that CEACAM1 is a substrate of the EGFR and that upon being phosphorylated, CEACAM1 reduces EGFR-mediated growth of transfected Cos-7 and MCF-7 cells in response to EGF. Using transgenic mice overexpressing a phosphorylation-defective CEACAM1 mutant in liver (L-SACC1), we show that the effect of CEACAM1 on EGF-dependent cell proliferation is mediated by its ability to bind to and sequester Shc, thus uncoupling EGFR signaling from the ras/MAPK pathway. In L-SACC1 mice, we also show that impaired CEACAM1 phosphorylation leads to ligand-independent increase of EGFR-mediated cell proliferation. This appears to be secondary to visceral obesity and the metabolic syndrome, with increased levels of output of free fatty acids and heparin-binding EGF-like growth factor from the adipose tissue of the mice. Thus, L-SACC1 mice provide a model for the mechanistic link between increased cell proliferation in states of impaired metabolism and visceral obesity.
Journal of Clinical Investigation 11/2004; 114(7):944-52. · 15.39 Impact Factor
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Tong Dai,
George A Abou-Rjaily, Qusai Y Al-Share,
Yan Yang,
Mats A Fernström,
Anthony M Deangelis,
Abraham D Lee,
Lawrence Sweetman,
Antonino Amato,
Marzia Pasquali,
Gary D Lopaschuk,
Sandra K Erickson,
Sonia M Najjar
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ABSTRACT: Inactivation of CEACAM1 in L-SACC1 mice by a dominant-negative transgene in liver impairs insulin clearance and increases serum free fatty acid (FFA) levels, resulting in insulin resistance. The contribution of elevated FFAs in the pathogenesis of insulin resistance is herein investigated. Treatment of L-SACC1 female mice with carnitine restored plasma FFA content. Concomitantly, it normalized insulin levels without directly regulating receptor-mediated insulin internalization and prevented glucose tolerance in these mice. Similarly, treatment with nicotinic acid, a lipolysis inhibitor, restored insulin-stimulated receptor uptake in L-SACC1 mice. Taken together, these data suggest that chronic elevation in plasma FFAs levels contributes to the regulation of insulin metabolism and action in L-SACC1 mice.
Journal of Biological Chemistry 11/2004; 279(43):45155-61. · 4.77 Impact Factor
