title: Dapper1 attenuates hepatic gluconeogenesis and lipogenesis by activating PI3K/Akt signaling.
abstract: Studies have shown that hepatic insulin resistance, a disorder of glucose and lipid metabolism, plays a vital role in type 2 diabetes (T2D). To clarify the function of Dapper1 in glucose and lipid metabolism in the liver, we investigated the relationships between Dapper1 and adenosine triphosphate (ATP)- and Ca2+-mediated activation of PI3K/Akt. We observed a reduction in hepatic Dapper1 in db/db (mice that are homozygous for a spontaneous diabetes mutation) and HFD-induced diabetic mice with T2D. Hepatic overexpression of Dapper1 improved hyperglycemia, insulin resistance, and fatty liver. It also increased Akt (pAkt) signaling and repressed both gluconeogenesis and lipogenesis. Conversely, Ad-shDapper1-induced knockdown of hepatic Dapper1 promoted gluconeogenesis and lipogenesis. Furthermore, Dapper1 activated PI3K p110α/Akt in an insulin-independent manner by inducing ATP production and secretion in vitro. Blockade of P2 ATP receptors, the downstream phospholipase C (PLC), or the inositol triphosphate receptor (IP3R all reduced the Dapper1-induced increase in cytosolic free calcium and Dapper1-mediated PI3K/Akt activation, as did removal of calcium in the medium. In conclusion, Dapper1 attenuates hepatic gluconeogenesis and lipogenesis in T2D.
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Jian-Ren
authors.initials: JR
authors.lastname: Kuang
authors.affiliation: Department of Cardiovascular, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Leng
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiao-Tian
authors.initials: XT
authors.lastname: Lei
authors.affiliation: Department of Endocrinology, The First Affiliated Hospital of Third Military Medical University, Chongqing 400038, China. Electronic address: john161112@163.com.
authors.forename: Zi-Wen
authors.initials: ZW
authors.lastname: Liang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000378:metabolism; D059305:Diet, High-Fat; D005215:Fasting / Q000097:blood; D005234:Fatty Liver / Q000097:blood / Q000150:complications / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis; D056945:Hep G2 Cells; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000150:complications / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016601:RNA-Binding Proteins; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate; D001786:Blood Glucose; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D018048:Receptors, Purinergic P2; C491683:DACT1 protein, human; C508545:frodo protein, mouse
keywords: Dapper1; Diabetes mice; Gluconeogenesis; Lipogenesis; PI3K/Akt; Type 2 diabetes