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.
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.
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.
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.
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)
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Published online: January 31, 2015
Accepted: January 18, 2015
Received in revised form: January 14, 2015
Received: December 5, 2014
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.