Dapper1 attenuates hepatic gluconeogenesis and lipogenesis by activating PI3K/Akt signaling

Mol Cell Endocrinol. 2017 May 15;447:106-115. doi: 10.1016/j.mce.2017.02.028. Epub 2017 Feb 24.

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.

Keywords: Dapper1; Diabetes mice; Gluconeogenesis; Lipogenesis; PI3K/Akt; Type 2 diabetes.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism
  • Diet, High-Fat
  • Fasting / blood
  • Fatty Liver / blood
  • Fatty Liver / complications
  • Fatty Liver / metabolism
  • Gene Knockdown Techniques
  • Gluconeogenesis*
  • Hep G2 Cells
  • Humans
  • Hyperglycemia / blood
  • Hyperglycemia / complications
  • Hyperglycemia / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipogenesis*
  • Liver / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Obese
  • Nuclear Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA-Binding Proteins
  • Receptors, Purinergic P2 / metabolism
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • Blood Glucose
  • DACT1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Receptors, Purinergic P2
  • frodo protein, mouse
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-akt