GLP-1 Receptor Activation Indirectly Reduces Hepatic Lipid Accumulation But Does Not Attenuate Development of Atherosclerosis in Diabetic Male ApoE-/- Mice

被引:298
作者
Panjwani, Naim [1 ]
Mulvihill, Erin E. [1 ]
Longuet, Christine [1 ]
Yusta, Bernardo [1 ]
Campbell, Jonathan E. [1 ]
Brown, Theodore J. [2 ]
Streutker, Catherine [3 ]
Holland, Dianne [1 ]
Cao, Xiemin [1 ]
Baggio, Laurie L. [1 ]
Drucker, Daniel J. [1 ]
机构
[1] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Med, Toronto, ON M5G 1X5, Canada
[2] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Dept Physiol, Toronto, ON M5G 1X5, Canada
[3] Univ Toronto, St Michaels Hosp, Dept Lab Med, Toronto, ON M5B 1W8, Canada
关键词
GLUCAGON-LIKE PEPTIDE-1; DIPEPTIDYL PEPTIDASE-4 INHIBITOR; INSULIN-RESISTANCE; MYOCARDIAL-INFARCTION; TISSUE DISTRIBUTION; MOUSE MODEL; AGONIST; STEATOSIS; CELLS; HYPERGLYCEMIA;
D O I
10.1210/en.2012-1937
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce lipid accumulation in peripheral tissues, attenuating atherosclerosis and hepatic steatosis in preclinical studies. We examined whether GLP-1R activation decreases atherosclerosis progression in high-fat diet-fed male ApoE(-/-) mice after administration of streptozotocin and treatment with the long-acting GLP-1R agonist taspoglutide administered once monthly vs. metformin in the drinking water for 12 wk. Taspoglutide did not reduce plaque area or lipid content in the aortic arch or abdominal aorta, and no significant change in aortic macrophage accumulation was detected after taspoglutide or metformin. In contrast, hepatic triglyceride levels were significantly reduced in livers from taspoglutide-treated mice. Both peripheral and intracerebroventricular administration of exendin-4 rapidly decreased plasma triglyceride levels in fasted mice, and taspoglutide therapy in ApoE(-/-) mice modulated the expression of hepatic genes controlling fatty acid uptake and oxidation. We were unable to detect expression of the entire Glp1r coding sequence in macrophages isolated from ApoE(-/-), C57BL/6, and IL10(-/-) mice. Similarly, Glp1r mRNA transcripts were not detected in RNA from isolated murine hepatocytes. Using Western blotting and tissue extracts from Glp1r(+/+) and Glp1r(-/-) mice, and cells transfected with a tagged murine GLP-1R cDNA, we could not validate the sensitivity and specificity of three different GLP-1R antisera commonly used for the detection of GLP-1R protein. Taken together, these findings illustrate divergent actions of GLP-1R agonists on atherosclerosis progression and accumulation of ectopic lipid in ApoE(-/-) mice and highlight the importance of indirect GLP-1R actions for the control of hepatic lipid accumulation. (Endocrinology 154: 127-139, 2013)
引用
收藏
页码:127 / 139
页数:13
相关论文
共 49 条
  • [1] Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4
    Arakawa, Masayuki
    Mita, Tomoya
    Azuma, Kosuke
    Ebato, Chie
    Goto, Hiromasa
    Nomiyama, Takashi
    Fujitani, Yoshio
    Hirose, Takahisa
    Kawamori, Ryuzo
    Watada, Hirotaka
    [J]. DIABETES, 2010, 59 (04) : 1030 - 1037
  • [2] Exendin-4 Promotes Liver Cell Proliferation and Enhances the PDX-1-induced Liver to Pancreas Transdifferentiation Process
    Aviv, Vered
    Meivar-Levy, Irit
    Rachmut, Itzhak H.
    Rubinek, Tamar
    Mor, Eytan
    Ferber, Sarah
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (48) : 33509 - 33520
  • [3] An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose Homeostasis
    Baggio, Laurie L.
    Huang, Qingling
    Cao, Xiemin
    Drucker, Daniel J.
    [J]. GASTROENTEROLOGY, 2008, 134 (04) : 1137 - 1147
  • [4] A recombinant human glucagon-like peptide (GLP)-1-albumin protein (Albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis
    Baggio, LL
    Huang, QL
    Brown, TJ
    Drucker, DJ
    [J]. DIABETES, 2004, 53 (09) : 2492 - 2500
  • [5] Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase
    Ben-Shlomo, Shani
    Zvibel, Isabel
    Shnell, Mati
    Shlomai, Amir
    Chepurko, Elena
    Halpern, Zamir
    Barzilai, Nir
    Oren, Ran
    Fishman, Sigal
    [J]. JOURNAL OF HEPATOLOGY, 2011, 54 (06) : 1214 - 1223
  • [6] Insulin Resistance, Hyperglycemia, and Atherosclerosis
    Bornfeldt, Karin E.
    Tabas, Ira
    [J]. CELL METABOLISM, 2011, 14 (05) : 575 - 585
  • [7] Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor
    Bullock, BP
    Heller, RS
    Habener, JF
    [J]. ENDOCRINOLOGY, 1996, 137 (07) : 2968 - 2978
  • [8] Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice
    Burmeister, Melissa A.
    Ferre, Tura
    Ayala, Jennifer E.
    King, Emily M.
    Holt, Rochelle M.
    Ayala, Julio E.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2012, 302 (03): : E334 - E343
  • [9] Daugherty Alan, 2003, Methods Mol Biol, V209, P293
  • [10] Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice
    Ding, XK
    Saxena, NK
    Lin, SB
    Gupta, N
    Anania, FA
    [J]. HEPATOLOGY, 2006, 43 (01) : 173 - 181