Article ; Online: Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance.
2015 Volume 63, Issue 2, Page(s) 477–485
Abstract: 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- ... ...
| Abstract | 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. |
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| MeSH term(s) | Animals ; Biopsy ; Blotting, Western ; Cells, Cultured ; Disease Models, Animal ; Gene Expression Regulation ; Humans ; Insulin Resistance/genetics ; Lipid Metabolism ; Liver/metabolism ; Liver/pathology ; Male ; Membrane Proteins/biosynthesis ; Membrane Proteins/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Non-alcoholic Fatty Liver Disease/genetics ; Non-alcoholic Fatty Liver Disease/metabolism ; RNA/genetics ; Reverse Transcriptase Polymerase Chain Reaction |
| Chemical Substances | Membrane Proteins ; Tiarp protein, mouse ; RNA (63231-63-0) |
| Language | English |
| Publishing date | 2015-08 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 605953-3 |
| ISSN | 1600-0641 ; 0168-8278 |
| ISSN (online) | 1600-0641 |
| ISSN | 0168-8278 |
| DOI | 10.1016/j.jhep.2015.01.025 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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