Research Article| Volume 63, ISSUE 2, P477-485, August 2015

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Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance

Published:January 31, 2015DOI:

      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.

      Graphical abstract


      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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        • Berlanga A.
        • Guiu-Jurado E.
        • Porras J.A.
        • Auguet T.
        Molecular pathways in non-alcoholic fatty liver disease.
        Clin Exp Gastroenterol. 2014; 7: 221-239
        • Day C.P.
        • James O.F.
        Steatohepatitis: a tale of two “hits”?.
        Gastroenterology. 1998; 114: 842-845
        • Anstee Q.M.
        • Goldin R.D.
        Mouse models in non-alcoholic fatty liver disease and steatohepatitis research.
        Int J Exp Pathol. 2006; 87: 1-16
        • Tilg H.
        • Moschen A.R.
        Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.
        Hepatology. 2010; 52: 1836-1846
        • Neuschwander-Tetri B.A.
        Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.
        Hepatology. 2010; 52: 774-788
        • Feldstein A.E.
        Novel insights into the pathophysiology of nonalcoholic fatty liver disease.
        Semin Liver Dis. 2010; 30: 391-401
        • Koppe S.W.
        Obesity and the liver: nonalcoholic fatty liver disease.
        Transl Res. 2014; 164: 312-322
        • Sanyal A.J.
        • Campbell-Sargent C.
        • Mirshahi F.
        • Rizzo W.B.
        • Contos M.J.
        • Sterling R.K.
        • et al.
        Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.
        Gastroenterology. 2001; 120: 1183-1192
        • Patki V.
        • Buxton J.
        • Chawla A.
        • Lifshitz L.
        • Fogarty K.
        • Carrington W.
        • et al.
        Insulin action on GLUT4 traffic visualized in single 3T3-l1 adipocytes by using ultra-fast microscopy.
        Mol Biol Cell. 2001; 12: 129-141
        • Ohgami R.S.
        • Campagna D.R.
        • McDonald A.
        • Fleming M.D.
        The Steap proteins are metalloreductases.
        Blood. 2006; 108: 1388-1394
        • Korkmaz C.G.
        • Korkmaz K.S.
        • Kurys P.
        • Elbi C.
        • Wang L.
        • Klokk T.I.
        • et al.
        Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer.
        Oncogene. 2005; 24: 4934-4945
        • Wellen K.E.
        • Fucho R.
        • Gregor M.F.
        • Furuhashi M.
        • Morgan C.
        • Lindstad T.
        • et al.
        Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis.
        Cell. 2007; 129: 537-548
        • Waki H.
        • Tontonoz P.
        STAMPing out inflammation.
        Cell. 2007; 129: 451-452
        • Abedini A.
        • Shoelson S.E.
        Inflammation and obesity: STAMPing out insulin resistance?.
        Immunol Cell Biol. 2007; 85: 399-400
        • Yoo S.K.
        • Cheong J.
        • Kim H.Y.
        STAMPing into mitochondria.
        Int J Biol Sci. 2014; 10: 321-326
        • Han L.
        • Tang M.X.
        • Ti Y.
        • Wang Z.H.
        • Wang J.
        • Ding W.Y.
        • et al.
        Overexpressing STAMP2 improves insulin resistance in diabetic ApoE(−)/(−)/LDLR(−)/(−) mice via macrophage polarization shift in adipose tissues.
        PLoS One. 2013; 8: e78903
        • Kim H.Y.
        • Cho H.K.
        • Yoo S.K.
        • Cheong J.H.
        Hepatic STAMP2 decreases hepatitis B virus X protein-associated metabolic deregulation.
        Exp Mol Med. 2012; 44: 622-632
        • Brunt E.M.
        • Kleiner D.E.
        • Wilson L.A.
        • Belt P.
        • Neuschwander-Tetri B.A.
        Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings.
        Hepatology. 2011; 53: 810-820
        • Kim K.H.
        • Shin H.J.
        • Kim K.
        • Choi H.M.
        • Rhee S.H.
        • Moon H.B.
        • et al.
        Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma.
        Gastroenterology. 2007; 132: 1955-1967
        • Edgerton D.S.
        • Ramnanan C.J.
        • Grueter C.A.
        • Johnson K.M.
        • Lautz M.
        • Neal D.W.
        • et al.
        Effects of insulin on the metabolic control of hepatic gluconeogenesis in vivo.
        Diabetes. 2009; 58: 2766-2775
        • Qin D.N.
        • Kou C.Z.
        • Ni Y.H.
        • Zhang C.M.
        • Zhu J.G.
        • Zhu C.
        • et al.
        Monoclonal antibody to the six-transmembrane epithelial antigen of prostate 4 promotes apoptosis and inhibits proliferation and glucose uptake in human adipocytes.
        Int J Mol Med. 2010; 26: 803-811
        • Chen X.
        • Zhu C.
        • Ji C.
        • Zhao Y.
        • Zhang C.
        • Chen F.
        • et al.
        STEAP4, a gene associated with insulin sensitivity, is regulated by several adipokines in human adipocytes.
        Int J Mol Med. 2010; 25: 361-367
        • ten Freyhaus H.
        • Calay E.S.
        • Yalcin A.
        • Vallerie S.N.
        • Yang L.
        • Calay Z.Z.
        • et al.
        Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.
        Cell Metab. 2012; 16: 81-89
        • Matsusue K.
        • Haluzik M.
        • Lambert G.
        • Yim S.H.
        • Gavrilova O.
        • Ward J.M.
        • et al.
        Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes.
        J Clin Invest. 2003; 111: 737-747
        • Sikkeland J.
        • Saatcioglu F.
        Differential expression and function of stamp family proteins in adipocyte differentiation.
        PLoS One. 2013; 8: e68249
        • Cheng R.
        • Qiu J.
        • Zhou X.Y.
        • Chen X.H.
        • Zhu C.
        • Qin D.N.
        • et al.
        Knockdown of STEAP4 inhibits insulin-stimulated glucose transport and GLUT4 translocation via attenuated phosphorylation of Akt, independent of the effects of EEA1.
        Mol Med Rep. 2011; 4: 519-523
        • Qin D.
        • Zhu J.
        • Ji C.
        • Kou C.
        • Zhu G.
        • Zhang C.
        • et al.
        Monoclonal antibody to six transmembrane epithelial antigen of prostate-4 influences insulin sensitivity by attenuating phosphorylation of P13K (P85) and Akt: Possible mitochondrial mechanism.
        J Bioenerg Biomembr. 2011; 43: 247-255
        • Fasshauer M.
        • Klein J.
        • Krahlisch S.
        • Lossner U.
        • Klier M.
        • Bluher M.
        • et al.
        GH is a positive regulator of tumor necrosis factor alpha-induced adipose related protein in 3T3-L1 adipocytes.
        J Endocrinol. 2003; 178: 523-531