Background & Aims
Most studies on the role of STAMP2 in metabolism have used adipose tissue. Little
knowledge exists concerning the role of STAMP2 in the liver, which is a metabolically
central target. We hypothesized that STAMP2 is involved in non-alcoholic fatty liver
disease (NAFLD) pathogenesis.
Methods
We examined our hypothesis using human NAFLD patient pathology samples and a high-fat
diet (HFD)-induced NAFLD mouse model. The molecular mechanism underlying hepatic STAMP2-mediated
lipid imbalance was explored using an oleic acid (OA)-induced NAFLD in vitro model.
Results
Noticeably, the expression level of STAMP2 protein was reduced in the livers obtained
from NAFLD patients and HFD-induced NAFLD mice. In vivo knockdown of hepatic STAMP2 by siRNA accelerated hepatic steatosis and insulin resistance
in mice fed a HFD. Conversely, the delivery of adenoviral STAMP2 (Ad-STAMP2) improved
hepatic steatosis in HFD-induced NAFLD mice. The expression of lipogenic or adipogenic
factors was increased in both in vitro and in vivo NAFLD models but was reversed by Ad-STAMP2. Adenoviral overexpression of STAMP2 improved
insulin resistance in the HFD-induced NAFLD mice. In vivo and in vitro assays demonstrated that STAMP2 modulates insulin sensitivity and glucose metabolism
and that STAMP2 counteracts OA-induced insulin resistance by modulating insulin receptor
substrate-1 stability.
Conclusions
The present study revealed that hepatic STAMP2 plays a pivotal role in preventing
HFD-induced NAFLD and that STAMP2 overexpression improves hepatic steatosis and insulin
resistance in NAFLD. Our findings indicate that STAMP2 may represent a suitable target
for interventions targeting NAFLD.
Graphical abstract
Graphical Abstract
Abbreviations:
STAMP2 (Six-transmembrane protein of prostate 2), NAFLD (non-alcoholic fatty liver disease), HFD (high-fat diet), OA (oleic acid), Ad-STAMP2 (adenoviral STAMP2), NASH (non-alcoholic steatohepatitis), FFAs (free fatty acids), SREBP-1c (sterol regulatory element-binding protein-1c), FAS (fatty acid synthase), PPARγ (peroxisome proliferator-activated receptor γ), SCD1 (hepatic stearoyl-CoA desaturase 1), A-FABP (adipocyte fatty acid–binding protein (also known as FABP-4 or aP2)), ACC1 (acetyl coenzyme A carboxylase-1), PI3K (phosphatidylinositol 3-kinase), IRS1 (insulin receptor substrate1), STEAP4 (six-transmembrane epithelial antigen of prostate 4), SD (standard diet), PFU (plaque-forming units), GTT (glucose tolerance test), ITT (insulin tolerance test), TC (total cholesterol), TG (triglyceride), NEFA (nonesterified fatty acids), C/EBPα (CAAT/enhancing binding protein alpha)Keywords
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Article info
Publication history
Published online: January 31, 2015
Accepted:
January 18,
2015
Received in revised form:
January 14,
2015
Received:
December 5,
2014
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
