Decreased carboxylesterases expression and hydrolytic activity in type 2 diabetic mice through Akt/mTOR/HIF-1α/Stra13 pathway

Xenobiotica. 2015;45(9):782-93. doi: 10.3109/00498254.2015.1020353. Epub 2015 Jul 27.

Abstract

1. This study investigated the alteration of carboxylesterases in type 2 diabetes. We found that the carboxylesterase 1d (Ces1d) and carboxylesterase 1e (Ces1e) expression and the capacity of hydrolytic activity of liver and intestine decreased, whereas the Akt/mTOR/HIF-1α/ Stra13 (DEC1) signaling was activated in T2D mice. Consistently, high insulin could give rise to the same results in the high-glucose DMEM condition, which mimicked T2D, in primary mouse hepatocytes. 2. Perifosine or rapamycin almost abolished the decrease of the Ces1d and Ces1e expression and the hydrolytic activity induced by the insulin in the primary mouse hepatocytes. 3. The responsiveness of human hepatoma (HepG2) cells to high insulin in high-glucose condition was similar to that of primary mouse hepatocytes in terms of the altered expression of carboxylesterases. 4. The knockdown of HIF-1α or DEC1 with shRNA construct abrogated the decrease of the CES1 and CES2 expression induced by the insulin in high glucose condition in HepG2 cells. 5. Taken together, the decreased carboxylesterases expression and hydrolytic activity in T2D mice are through the Akt/mTOR/HIF-1α/Stra13 (DEC1) pathway.

Keywords: Akt/mTOR/HIF-1α/Stra13 pathway; carboxylesterase 1d (Ces1d); carboxylesterase 1e (Ces1e); insulin; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Blood Glucose / metabolism
  • Carboxylic Ester Hydrolases / genetics
  • Carboxylic Ester Hydrolases / metabolism*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / enzymology*
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Glucose / pharmacology
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Homeodomain Proteins / metabolism*
  • Humans
  • Hydrolysis
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Insulin / metabolism
  • Insulin / pharmacology
  • Intestines / drug effects
  • Intestines / enzymology
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Mice, Inbred C57BL
  • Overweight / blood
  • Overweight / complications
  • Phosphorylcholine / analogs & derivatives
  • Phosphorylcholine / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Signal Transduction* / drug effects
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlhe40 protein, mouse
  • Blood Glucose
  • Homeodomain Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin
  • RNA, Messenger
  • RNA, Small Interfering
  • Phosphorylcholine
  • perifosine
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Carboxylic Ester Hydrolases
  • Glucose
  • Sirolimus