The obesogenic effects of polyunsaturated fatty acids are dependent ...

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JBC Papers in Press. Published on June 16, 2011 as Manuscript M111.234732 The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.M111.234732 Nutritional Regulation of Bile Acid Metabolism is Associated with Improved Pathological Characteristics of the Metabolic Syndrome Bjørn Liaset 1* , Qin Hao 2 , Henry Jørgensen 3 , Philip Hallenborg 4 , Zhen-Yu Du 1 , Tao Ma 2 , Hanns- Ulrich Marschall 5 , Mogens Kruhøffer 6 , Ruiqiang Li 7 , Qibin Li 7 , Christian Clement Yde 3 , Gabriel Criales 1 , Hanne C. Bertram 8 , Gunnar Mellgren 9, 10 , Erik Snorre Øfjord 11 , Erik-Jan Lock 1 , Marit Espe 1 , Livar Frøyland 1 , Lise Madsen 1,2 , Karsten Kristiansen 2* 1 National Institute of Nutrition and Seafood Research, Bergen, Norway, 2 Department of Biology, University of Copenhagen, Denmark, 3 Department of Animal Health, Welfare and Nutrition, Aarhus University , Denmark, 4 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark, 5 Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden, 6 AROS Applied Biotechnology, Aarhus, Denmark, 7 Beijing Genomic Institute, Shenzhen, Peoples Republic of China, 8 Department of Food Science, Aarhus University, Denmark, 9 Institute of Medicine, University of Bergen, Norway, 10 Hormone Laboratory, Haukeland University Hospital, Norway, 11 Center for Clinical Trials, Bergen, Norway. *Correspondence to: Bjørn Liaset, National Institute of Nutrition and Seafood Research, P.O. Box 2029 Nordnes, N-5817 Bergen, Norway. Fax: +47 55 90 52 99; Phone: +47 46 81 12 97; E-mail: bli@nifes.no or Karsten Kristiansen, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark. Fax +45 3522 2128; Phone +45 6011 2408; E mail: kk@bio.ku.dk Running title: Bile acid metabolism is regulated by dietary protein source Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacyl glycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to dietinduced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels, and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1α and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and 1 subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased wholebody energy expenditure and heat dissipation. In skeletal muscle, expressions of the PPARβ/δ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5wt% cholestyramine to the high-fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG and the decrease in non-fasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet, and that such modulation may prevent/ameliorate characteristic features of the metabolic syndrome. Downloaded from www.jbc.org by guest, on July 7, 2011 Copyright 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Bile acids (BAs) are synthesized in the liver from cholesterol. After their synthesis, they are conjugated to the amino acids taurine or glycine in a species-dependent manner (1). Conjugation of bile acids increases their solubility and facilitates their secretion into bile (2). In the intestine, the bile acids aid in the absorption of lipophilic nutrients (3). Normally, the bile acids are efficiently taken up by the enterocytes of the small intestine, transported back to the liver, and are thus conserved through the enterohepatic circulation (4). Bile acids are activators of the nuclear receptor farnesoid X receptor α (Fxr/Nr1h4) (5-7). The main physiological role of Fxr is to maintain bile acid homeostasis and to regulate genes encoding enzymes involved in bile acid synthesis and transport. In addition to bile acid homeostasis, Fxr is important for normal lipid metabolism. Fxr -/- mice display higher triacylglycerol (TAG) concentrations in serum and liver (8,9) and have an increased synthesis of apolipoprotein (Apo) B-containing lipoproteins (9). In line with these findings, bile acid treatment has been reported, in a Fxrdependent manner, to induce liver very-lowdensity lipoprotein receptor (Vldlr) transcription (10) and to prevent hepatic TAG accumulation, VLDL secretion and elevated serum TAG concentration in mice (11). Thus, bile acids and Fxr play central roles in VLDL lipoprotein metabolism and in the control of TAG levels. Glucose metabolism is also regulated by bile acids and mice treated with cholic acid are protected from diet-induced hyperglycemia (12) and have down-regulated liver expression of the gluconeogenic phosphoenolpyruvate carboxykinase (Pck1) gene (13,14). Furthermore, Fxr -/- mice are glucose intolerant and insulin resistant, and insulin signaling is blunted in several tissues (15-17). Activation of Fxr with a synthetic ligand, GW4064, or hepatic over-expression of constitutively active Fxr lowered blood glucose in both diabetic db/db and wild-type mice (15). It is therefore evident that bile acid signaling and Fxr function are essential for normal glucose regulation. Bile acids are also endogenous activators of the G-protein coupled receptor Tgr5 (also referred to as GB37/ M-BAR/ Gpbar1) (18,19). Stimulation of Tgr5 by bile 2 acids has been shown to increase energy expenditure and to protect mice from dietinduced obesity and glucose intolerance (20). Consistent with the role of Tgr5 in the control of energy expenditure, female Tgr5 -/- mice show increased adiposity when challenged with a high fat diet (21). Also, Tgr5 activation by bile acids has been reported to promote production and release of glucagon-like peptide 1 (GLP-1) in enteroendocrine cell lines (22) and in mice (23), adding another aspect of bile acid treatment for the prevention of dietinduced glucose intolerance and insulin resistance. Thus, bile acid signaling through Tgr5 might be important for the maintenance of normal energy homeostasis and insulin sensitivity. The benefits of activating Tgr5 or Fxr for the prevention of the metabolic syndrome have stimulated the development of synthetic ligands for these receptors (24,25). Another strategy to increase Tgr5 and/or Fxr signaling would be to alter endogenous BA metabolism. As hepatic bile acid conjugation is important for secretion of BAs into bile (2), and rats conjugate BAs to both taurine and glycine with high efficiency (26), the dietary levels of these amino acids might be crucial for BA conjugation and secretion (27). Feeding rats casein-based diets supplemented with either glycine or taurine led to reduced plasma cholesterol and liver TAG concentrations, whereas only taurine supplementation reduced plasma TAG levels (28). Furthermore, taurine administration has been reported to induce hepatic protein expression of the canalicular transporter proteins ATP-binding-cassette b11, Abcb11 (also called Bsep) and Abcc2 (also called Mrp2). Concomitantly, bile flow and taurocholate excretion was induced in experiments with perfused rat livers (29). In rats fed low-fat diets, we have previously shown that BA metabolism can be modulated by dietary proteins with different endogenous glycine and taurine contents (30). Thus, evidence is accumulating that BA metabolism can be modulated by dietary levels of glycine and taurine in normal-energy diets. However, development of the metabolic syndrome is tightly associated with intake of energy-dense diets. Therefore, the present study was undertaken in order to test the hypothesisis that rats treated with a taurineand glycine-rich protein source, salmon protein Downloaded from www.jbc.org by guest, on July 7, 2011
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The obesogenic effects of polyunsat
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Table of Contents Acknowledgement .
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Abstract in Danish Polyumættede n-
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Polyunsaturated fatty acids in the
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was more than 3 times higher in the
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gluconeogenesis and ureagenesis (Fi
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high dietary PUFAs, the modulation
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In a pair of population studies, an
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18. Massiera, F. et al. Arachidonic
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54. Xu, J. et al. Polyunsaturated f
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Annexes 1. Ma T, Liaset B, Hao Q, P
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Fish Oil, Sucrose and Obesity Obesi
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Fish Oil, Sucrose and Obesity Figur
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Fish Oil, Sucrose and Obesity Table
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Fish Oil, Sucrose and Obesity 6. Ma
Page 35 and 36: Carbohydrate source and insulin sec
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Page 51 and 52: 350 351 FIGURE LEGENDS 352 353 354
Page 53 and 54: 398 399 400 401 402 403 404 subunit
Page 55 and 56: 446 447 448 449 450 451 gamma, coac
Page 57 and 58: 484 485 486 TABLE 1. Macronutrient
Page 59 and 60: Energy (kJ/g) 17.16 25.12 25.12 25.
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Page 74 and 75: Cyclooxygenases and UCP1 Although i
Page 76 and 77: Cyclooxygenases and UCP1 Figure 2.
Page 78 and 79: Cyclooxygenases and UCP1 Figure 4.
Page 80 and 81: Cyclooxygenases and UCP1 PLoS ONE |
Page 82 and 83: Cyclooxygenases and UCP1 E synthase
Page 84 and 85: Cyclooxygenases and UCP1 29. Granne
Page 88 and 89: hydrolysate (SPH), would be protect
Page 90 and 91: was used as the liver cytosolic fra
Page 92 and 93: In order to demonstrate that bile a
Page 94 and 95: Nutritional regulation of endogenou
Page 96 and 97: in increased whole body energy expe
Page 98 and 99: 38. Kanehisa M, and Goto S. (2000)
Page 100 and 101: FOOTNOTES This work was carried out
Page 102 and 103: fed the same diets, plus the SPH-di
Page 104 and 105: Figure 2 A nmol/ min/ mg prot 2,4 1
Page 106 and 107: Figure 4 A 6 Liver Pparα B 21 Live
Page 108 and 109: Figure 7 A Plasma ALAT B Liver Ucp2
Page 110 and 111: Ruzzin et al. investigated the meta
Page 112 and 113: Ruzzin et al. CD14, and rho kinases
Page 114 and 115: Ruzzin et al. salmon oil induced a
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