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  • Original Article
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Animal Models

RETRACTED ARTICLE: Adiponectin deficiency rescues high-fat diet-induced hepatic injury, apoptosis and autophagy loss despite persistent steatosis

International Journal of Obesity volume 41, pages 1403–1412 (2017)Cite this article

Subjects

This article was retracted on 17 October 2022

This article has been updated

Abstract

Background & aims:

Low levels of adiponectin (APN), an adipose-derived adipokine, are associated with obesity and non-alcoholic steatohepatitis although its role in high-fat diet-induced hepatic injury and steatosis remains unclear. Here we hypothesized that APN deficiency alters fat diet-induced hepatic function. To this end, we examined the effect of APN deficiency on high-fat diet-induced hepatic injury, apoptosis and steatosis.

Methods:

Adult wild type and APN knockout mice were fed a low- or high-fat diet for 20 weeks. Serum levels of liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, hepatic triglycerides, steatosis, pro-inflammatory cytokines, apoptosis and autophagy were examined.

Results:

High-fat feeding led to elevated body (48.2%) and liver weights (18.8%), increased levels of ALT (87.8%), serum cholesterol (104.4%), hepatic triglycerides (305.6%) and hepatic fat deposition as evidenced by Oil Red O staining, along with a reduced AST/ALT ratio and unchanged AST. Although APN knockout itself did not affect hepatic function and morphology, it reconciled fat diet-induced hepatic injury (P<0.05 vs WT-HF group) without reversing changes in body and liver weights, serum cholesterol and hepatic steatosis. In addition, fat diet intake promoted AMPK phosphorylation, p62 accumulation and apoptosis, including elevated Bax and cleaved Caspase-3 and downregulated Bcl-2, along with suppressed phosphorylation of Akt, STAT3 and JNK, and the autophagy makers Atg7, Beclin-1 and LC3B (P<0.05 vs WT-LF group) without affecting hepatic interlelukin-6 and tumor necrosis factor-α levels, the effects were reversed or significantly attenuated by APN knockout (P<0.05 vs WT-HF group). In vitro study using HepG2 cells revealed that STAT3 activation rescued palmitic acid-induced cell injury whereas STAT3 inhibition nullified APN knockdown-offered beneficial effects.

Conclusions:

Our results revealed that high-fat diet intake promotes hepatic steatosis, apoptosis and interrupted autophagy. APN knockout elicits protective effect against hepatic injury possibly associated with autophagy regulation despite persistent hepatic steatosis.

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References

  1. Baiceanu A, Mesdom P, Lagouge M, Foufelle F . Endoplasmic reticulum proteostasis in hepatic steatosis. Nat Rev Endocrinol 2016; 12: 710–722.

    Article  CAS  PubMed  Google Scholar 

  2. Yki-Jarvinen H . Diagnosis of non-alcoholic fatty liver disease (NAFLD). Diabetologia 2016; 59: 1104–1111.

    Article  CAS  PubMed  Google Scholar 

  3. Rinella ME . Nonalcoholic fatty liver disease: a systematic review. JAMA 2015; 313: 2263–2273.

    Article  CAS  PubMed  Google Scholar 

  4. Arguello G, Balboa E, Arrese M, Zanlungo S . Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim Biophys Acta 2015; 1852: 1765–1778.

    Article  CAS  PubMed  Google Scholar 

  5. Machado MV, Cortez-Pinto H . Diet, microbiota, obesity, and NAFLD: a dangerous quartet. Int J Mol Sci 2016; 17: 481.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Angulo P, Machado MV, Diehl AM . Fibrosis in nonalcoholic fatty liver disease: mechanisms and clinical implications. Semin Liver Dis 2015; 35: 132–145.

    Article  CAS  PubMed  Google Scholar 

  7. Byrne CD, Targher G . NAFLD: a multisystem disease. J Hepatol 2015; 62: S47–S64.

    Article  PubMed  Google Scholar 

  8. Wong VW, Chitturi S, Wong GL, Yu J, Chan HL, Farrell GC . Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol Hepatol 2016; 1: 56–67.

    Article  PubMed  Google Scholar 

  9. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT . American Gastroenterological Association Institute Technical Review on the role of elastography in chronic liver diseases. Gastroenterology 2017; 152: 1544–1577.

    Article  PubMed  Google Scholar 

  10. Noureddin M, Mato JM, Lu SC . Nonalcoholic fatty liver disease: update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine. Exp Biol Med (Maywood) 2015; 240: 809–820.

    Article  CAS  Google Scholar 

  11. Abd El-Kader SM, El-Den Ashmawy EM . Non-alcoholic fatty liver disease: the diagnosis and management. World J Hepatol 2015; 7: 846–858.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Listenberger LL, Han XL, Lewis SE, Cases S, Farese RV, Ory DS et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 2003; 100: 3077–3308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Choi SS, Diehl AM . Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol 2008; 19: 295–300.

    Article  CAS  PubMed  Google Scholar 

  14. Abenavoli L, Milic N, Di Renzo L, Preveden T, Medic-Stojanoska M, De Lorenzo A . Metabolic aspects of adult patients with nonalcoholic fatty liver disease. World J Gastroenterol 2016; 22: 7006–7016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vatner DF, Majumdar SK, Kumashiro N, Petersen MC, Rahimi Y, Gattu AK et al. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proc Natl Acad Sci USA 2015; 112: 1143–1148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Visser ME, Lammers NM, Nederveen AJ, van der Graaf M, Heerschap A, Ackermans MT et al. Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia. Diabetologia 2011; 54: 2113–2121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lonardo A, Lombardini S, Scaglioni F, Carulli L, Ricchi M, Ganazzi D et al. Hepatic steatosis and insulin resistance: does etiology make a difference? J Hepatol 2006; 44: 190–196.

    Article  CAS  PubMed  Google Scholar 

  18. Fabbrini E, Magkos F . Hepatic steatosis as a marker of metabolic dysfunction. Nutrients 2015; 7: 4995–5019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tilg H, Moschen AR . Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010; 52: 1836–1846.

    Article  CAS  PubMed  Google Scholar 

  20. Ruan H, Dong LQ . Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol 2016; 8: 101–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jiang C, Kim JH, Li F, Qu A, Gavrilova O, Shah YM et al. Hypoxia-inducible factor 1alpha regulates a SOCS3-STAT3-adiponectin signal transduction pathway in adipocytes. J Biol Chem 2013; 288: 3844–3857.

    Article  CAS  PubMed  Google Scholar 

  22. Ladyman SR, Grattan DR . JAK-STAT and feeding. JAK-STAT 2013; 2: e23675.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hirano T, Ishihara K, Hibi M . Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 2000; 19: 2548–2556.

    Article  CAS  PubMed  Google Scholar 

  24. Siddiquee KAZ, Turkson J . STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res 2008; 18: 254–267.

    Article  Google Scholar 

  25. Yu H, Lee H, Herrmann A, Buettner R, Jove R . Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 2014; 14: 736–746.

    Article  CAS  PubMed  Google Scholar 

  26. Gao S, Howard S, LoGrasso PV . Pharmacological inhibition of c-Jun N-terminal kinase reduces food intake and sensitizes leptin's anorectic signaling actions. Sci Rep 2017; 7: 41795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brown LA, Lee DE, Patton JF, Perry RA Jr., Brown JL, Baum JI et al. Diet-induced obesity alters anabolic signalling in mice at the onset of skeletal muscle regeneration. Acta Physiol (Oxf) 2015; 215: 46–57.

    Article  CAS  PubMed  Google Scholar 

  28. Kim BH, Han S, Lee H, Park CH, Chung YM, Shin K et al. Metformin enhances the anti-adipogenic effects of atorvastatin via modulation of STAT3 and TGF-beta/Smad3 signaling. Biochem Biophys Res Commun 2015; 456: 173–178.

    Article  CAS  PubMed  Google Scholar 

  29. Dinh CH, Szabo A, Camer D, Yu Y, Wang H, Huang XF . Bardoxolone methyl prevents fat deposition and inflammation in the visceral fat of mice fed a high-fat diet. Chem Biol Interact 2015; 229: 1–8.

    Article  CAS  PubMed  Google Scholar 

  30. You L, Wang Z, Li H, Shou J, Jing Z, Xie J et al. The role of STAT3 in autophagy. Autophagy 2015; 11: 729–739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Granato M, Rizzello C, Gilardini Montani MS, Cuomo L, Vitillo M, Santarelli R et al. Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways. J Nutr Biochem 2017; 41: 124–136.

    Article  CAS  PubMed  Google Scholar 

  32. Guo R, Xu X, Babcock SA, Zhang Y, Ren J . Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy. J Hepatol 2015; 62: 647–656.

    Article  CAS  PubMed  Google Scholar 

  33. Schust J, Sperl B, Hollis A, Mayer TU, Berg T . Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol 2006; 13: 1235–1242.

    Article  CAS  PubMed  Google Scholar 

  34. Chiba T, Yamada M, Hashimoto Y, Sato M, Sasabe J, Kita Y et al. Development of a femtomolar-acting humanin derivative named colivelin by attaching activity-dependent neurotrophic factor to its N terminus: characterization of colivelin-mediated neuroprotection against Alzheimer's disease-relevant insults in vitro and in vivo. J Neurosci 2005; 25: 10252–10261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sari Y, Chiba T, Yamada M, Rebec GV, Aiso S . A novel peptide, colivelin, prevents alcohol-induced apoptosis in fetal brain of C57BL/6 mice: signaling pathway investigations. Neuroscience 2009; 164: 1653–1664.

    Article  CAS  PubMed  Google Scholar 

  36. Sorbi D, Boynton J, Lindor KD . The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol 1999; 94: 1018–1022.

    Article  CAS  PubMed  Google Scholar 

  37. Bayard M, Holt J, Boroughs E . Nonalcoholic fatty liver disease. Am Fam Phys 2006; 73: 1961–1968.

    Google Scholar 

  38. Noureddin M, Rinella ME . Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015; 19: 361–379.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Dokladny K, Myers OB, Moseley PL . Heat shock response and autophagy—cooperation and control. Autophagy 2015; 11: 200–213.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Xu Y, Lv SX . The effect of JAK2 knockout on inhibition of liver tumor growth by inducing apoptosis, autophagy and anti-proliferation via STATs and PI3K/AKT signaling pathways. Biomed Pharmacother 2016; 84: 1202–1212.

    Article  CAS  PubMed  Google Scholar 

  41. Kim MO, Lee HS, Chin YW, Moon DO, Ahn JS . Gartanin induces autophagy through JNK activation which extenuates caspase-dependent apoptosis. Oncol Rep 2015; 34: 139–146.

    Article  CAS  PubMed  Google Scholar 

  42. Jonchere B, Belanger A, Guette C, Barre B, Coqueret O . STAT3 as a new autophagy regulator. JAK-STAT 2013; 2: e24353.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Habeeb BS, Kitayama J, Nagawa H . Adiponectin supports cell survival in glucose deprivation through enhancement of autophagic response in colorectal cancer cells. Cancer Sci 2011; 102: 999–1006.

    Article  CAS  PubMed  Google Scholar 

  44. Cowherd RB, Asmar MM, Alderman JM, Alderman EA, Garland AL, Busby WH et al. Adiponectin lowers glucose production by increasing SOGA. Am J Pathol 2010; 177: 1936–1945.

    Article  PubMed  Google Scholar 

  45. Trocoli A, Djavaheri-Mergny M . The complex interplay between autophagy and NF-kappaB signaling pathways in cancer cells. Am J Cancer Res 2011; 1: 629–649.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR . Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 2007; 21: 1396–1408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Amaro A, Fabbrini E, Kars M, Yue P, Schechtman K, Schonfeld G et al. Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 2010; 139: 149–153.

    Article  CAS  PubMed  Google Scholar 

  48. Della Corte C, Fintini D, Giordano U, Cappa M, Brufani C, Majo F et al. Fatty liver and insulin resistance in children with hypobetalipoproteinemia: the importance of aetiology. Clin Endocrinol 2013; 79: 49–54.

    Article  CAS  Google Scholar 

  49. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M et al. Autophagy regulates lipid metabolism. Nature 2009; 458: 1131–1135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Shimano M, Ouchi N, Shibata R, Ohashi K, Pimentel DR, Murohara T et al. Adiponectin deficiency exacerbates cardiac dysfunction following pressure overload through disruption of an AMPK-dependent angiogenic response. J Mol Cell Cardiol 2010; 49: 210–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Russo SB, Baicu CF, Van Laer A, Geng T, Kasiganesan H, Zile MR et al. Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J Clin Invest 2012; 122: 3919–3930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xu K, Yang Y, Yan M, Zhan J, Fu X, Zheng X . Autophagy plays a protective role in free cholesterol overload-induced death of smooth muscle cells. J Lipid Res 2010; 51: 2581–2590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Guo R, Zhang Y, Turdi S, Ren J . Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy. Biochim Biophys Acta 2013; 1832: 1136–1148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We appreciate the assistance from Dr Xihui Xu from University of Wyoming. This work was supported by NIH/NIGMS 8P20GM103432, NSFC 81370195 and NSFC 81522004.

Author contributions

RG: data collection; RG, SN, YZ and JR: study design, funding and manuscript writing.

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Authors and Affiliations

  1. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA

    R Guo, S Nair, Y Zhang & J Ren

  2. Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, PR China

    Y Zhang

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Correspondence to Y Zhang or J Ren.

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Guo, R., Nair, S., Zhang, Y. et al. RETRACTED ARTICLE: Adiponectin deficiency rescues high-fat diet-induced hepatic injury, apoptosis and autophagy loss despite persistent steatosis. Int J Obes 41, 1403–1412 (2017). https://doi.org/10.1038/ijo.2017.128

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