Skip to main content

Advertisement

SpringerLink
Log in

Adiponectin Stimulates Apolipoprotein A-1 Gene Expression in HepG2 Cells via AMPK, PPARα, and LXRs Signaling Mechanisms

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Adiponectin is an adipose tissue hormone, participating in energy metabolism and involved in atherogenesis. Previously, it was found that adiponectin increases expression of the APOA1 (apolipoprotein A-1) gene in hepatocytes, but the mechanisms of this effect remained unexplored. Our aim was to investigate the role of adiponectin receptors AdipoR1/R2, AMP-activated protein kinase (AMPK), nuclear peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptors (LXRs) in mediating the action of adiponectin on hepatic APOA1 expression in human hepatoma HepG2 cells. The level of APOA1 expression was determined by RT-qPCR and ELISA. We showed that the siRNA-mediated knockdown of genes coding for AdipoR1, AdipoR2, AMPK, PPARα, and LXRα and β prevented adiponectin-induced APOA1 expression in HepG2 cells and demonstrated that interaction of PPARα and LXRs with the APOA1 gene hepatic enhancer is important for the adiponectin-dependent APOA1 transcription. The results of this study point out to the involvement of both types of adiponectin receptors, AMPK, PPARα, and LXRs in the adiponectin-dependent upregulation of the APOA1 expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

Abbreviations

ApoA-1:

apolipoprotein A-1

AdipoR:

adiponectin receptor

AICAR:

5-aminoimidazole-4-carboxamide ribonucleotide

AMPK:

AMP-activated protein kinase

HDL:

high density lipoproteins

HE:

hepatocyte enhancer

HNF4α:

hepatocyte nuclear factor 4α

LKB-1:

hepatic kinase B1

LXR:

liver X receptor

siRNA:

small interfering RNA

PPAR:

peroxisome proliferator-activator receptor

RT-qPCR:

quantitative PCR with reverse transcription

TNFα:

tumor necrosis factor

References

  1. Berg, A. H., and Scherer, P. E. (2005) Adipose tissue, inflammation, and cardiovascular disease, Circ. Res., 96, 939-949, https://doi.org/10.1161/01.RES.0000163635.62927.34.

    Article  CAS  PubMed  Google Scholar 

  2. Matsuura, F., Oku, H., Koseki, M., Sandoval, J. C., Yuasa-Kawase, M., et al. (2007) Adiponectin accelerates reverse cholesterol transport by increasing high density lipoprotein assembly in the liver, Biochem. Biophys. Res. Commun., 358, 1091-1095, https://doi.org/10.1016/j.bbrc.2007.05.040.

    Article  CAS  PubMed  Google Scholar 

  3. Neumeier, M., Sigruener, A., Eggenhofer, E., Weigert, J., Weiss, T. S., et al. (2007) High molecular weight adiponectin reduces apolipoprotein B and E release in human hepatocytes, Biochem. Biophys. Res. Commun., 352, 543-548, https://doi.org/10.1016/j.bbrc.2006.11.058.

    Article  CAS  PubMed  Google Scholar 

  4. Qiao, L., Zou, C., van der Westhuyzen, D. R., and Shao, J. (2008) Adiponectin reduces plasma triglyceride by increasing VLDL triglyceride catabolism, Diabetes, 57, 1824-1833, https://doi.org/10.2337/db07-0435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tanyanskiy, D. A., Martynikhin, I. A., Rotar, O. P., Konradi, A. O., Sokolian, N. A., et al. (2015) Association of adipokines with metabolic disorders in patients with schizophrenia: results of comparative study with mental healthy cohort, Diabetes Metab. Syndr., 9, 163-167, https://doi.org/10.1016/j.dsx.2015.04.009.

    Article  PubMed  Google Scholar 

  6. Tschritter, O., Fritsche, A., Thamer, C., Haap, M., Shirkavand, F., et al. (2003) Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism, Diabetes, 52, 239-243, https://doi.org/10.2337/diabetes.52.2.239.

    Article  CAS  PubMed  Google Scholar 

  7. Malik, S., Karathanasis, S. K. (1996) TFIIB-directed transcriptional activation by the orphan nuclear receptor hepatocyte nuclear factor 4, Mol. Cell. Biol., 16, 1824-1831, https://doi.org/10.1128/mcb.16.4.1824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Martin, G., Duez, H., Blanquart, C., Berezowski, V., Poulain, P., et al. (2001) Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I, J. Clin. Invest., 107, 1423-1432, https://doi.org/10.1172/JCI10852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Huuskonen, J., Vishnu, M., Chau, P., Fielding, P. E., and Fielding, C. J. (2006) Liver X receptor inhibits the synthesis and secretion of apolipoprotein A1 by human liver-derived cells, Biochemistry, 45, 15068-15074, https://doi.org/10.1021/bi061378y.

    Article  CAS  PubMed  Google Scholar 

  10. Shavva, V. S., Mogilenko, D. A., Bogomolova, A. M., Nikitin, A. A., Dizhe, E. B., et al. (2016) PPARγ represses apolipoprotein A-I gene but impedes TNFα-mediated ApoA-I downregulation in HepG2 Cells, J. Cell. Biochem., 117, 2010-2022, https://doi.org/10.1002/jcb.25498.

    Article  CAS  PubMed  Google Scholar 

  11. Harnish, D. C., Malik, S., Kilbourne, E., Costa, R., and Karathanasis, S. K. (1996) Control of apolipoprotein AI gene expression through synergistic interactions between hepatocyte nuclear factors 3 and 4, J. Biol. Chem., 271, 13621-13628, https://doi.org/10.1074/jbc.271.23.13621.

    Article  CAS  PubMed  Google Scholar 

  12. Shavva, V. S., Bogomolova, A. M., Nikitin, A. A., Dizhe, E. B., Oleinikova, G. N., et al. (2017) FOXO1 and LXRα downregulate the apolipoprotein A-I gene expression during hydrogen peroxide-induced oxidative stress in HepG2 cells, Cell Stress Chaperones, 22, 123-134, https://doi.org/10.1007/s12192-016-0749-6.

    Article  CAS  PubMed  Google Scholar 

  13. Mogilenko, D. A., Dizhe, E. B., Shavva, V. S., Lapikov, I. A., Orlov, S. V., et al. (2009) Role of the nuclear receptors HNF4 alpha, PPAR alpha, and LXRs in the TNF alpha-mediated inhibition of human apolipoprotein A-I gene expression in HepG2 cells, Biochemistry, 48, 11950-11960, https://doi.org/10.1021/bi9015742.

    Article  CAS  PubMed  Google Scholar 

  14. Shavva, V. S., Bogomolova, A. M., Nikitin, A. A., Dizhe, E. B., Tanyanskiy, D. A., et al. (2017) Insulin-mediated downregulation of apolipoprotein A-I gene in Human hepatoma cell line HepG2: the role of interaction between FOXO1 and LXRβ transcription factors, J. Cell. Biochem., 118, 382-396, https://doi.org/10.1002/jcb.25651.

    Article  CAS  PubMed  Google Scholar 

  15. Wanninger, J., Neumeier, M., Weigert, J., Bauer, S., Weiss, T. S., et al. (2009) Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways, Am. J. Physiol. Gastrointest. Liver Physiol., 297, G611-G618, https://doi.org/10.1152/ajpgi.90644.2008.

    Article  CAS  PubMed  Google Scholar 

  16. Waki, H., Yamauchi, T., Kamon, J., Ito, Y., Uchida, S., et al. (2003) Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin, J. Biol. Chem., 278, 40352-40363, https://doi.org/10.1074/jbc.M300365200.

    Article  CAS  PubMed  Google Scholar 

  17. Yamauchi, T., Kamon, J., Ito, Y., Tsuchida, A., Yokomizo, T., et al. (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects, Nature, 423, 762-769, https://doi.org/10.1038/nature01705.

    Article  CAS  PubMed  Google Scholar 

  18. Yamauchi, T., Nio, Y., Maki, T., Kobayashi, M., Takazawa, T., et al. (2007) Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions, Nat. Med., 13, 332-339, https://doi.org/10.1038/nm1557.

    Article  CAS  PubMed  Google Scholar 

  19. Deepa, S. S., Zhou, L., Ryu, J., Wang, C., Mao, X., et al. (2011) APPL1 mediates adiponectin-induced LKB1 cytosolic localization through the PP2A-PKCzeta signaling pathway, Mol. Endocrinol., 25, 1773-1785, https://doi.org/10.1210/me.2011-0082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lee, J., Hong, S. W., Park, S. E., Rhee, E. J., Park, C. Y., et al. (2015) AMP-activated protein kinase suppresses the expression of LXR/SREBP-1 signaling-induced ANGPTL8 in HepG2 cells, Mol. Cell. Endocrinol., 414, 148-155, https://doi.org/10.1016/j.mce.2015.07.031.

    Article  CAS  PubMed  Google Scholar 

  21. Prieur, X., Schaap, F. G., Coste, H., and Rodríguez, J. C. (2005) Hepatocyte nuclear factor-4alpha regulates the human apolipoprotein AV gene: identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1alpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway, Mol. Endocrinol., 19, 3107-3125, https://doi.org/10.1210/me.2005-0048.

    Article  CAS  PubMed  Google Scholar 

  22. Hwahng, S. H., Ki, S. H., Bae, E. J., Kim, H. E., and Kim, S. G. (2009) Role of adenosine monophosphate-activated protein kinase-p70 ribosomal S6 kinase-1 pathway in repression of liver X receptor-alpha-dependent lipogenic gene induction and hepatic steatosis by a novel class of dithiolethiones, Hepatology, 49, 1913-1925, https://doi.org/10.1002/hep.22887.

    Article  CAS  PubMed  Google Scholar 

  23. Tanyanskiy, D. A., Dizhe, E. B., Oleinikova, G. N., Shavva, V. S., and Denisenko, A. D. (2021) Mechanisms of the influence of adiponectin on apolipoproteins A-1 and B production by human hepatocytes, Med. Acad. J., 21, 39-45, https://doi.org/10.17816/MAJ62892.

    Article  Google Scholar 

  24. Dizhe, E. B., Ignatovich, I. A., Burov, S. V., Pohvoscheva, A. V., Akifiev, B. N., et al. (2006) Complexes of DNA with cationic peptides: conditions of formation and factors effecting internalization by mammalian cells, Biochemistry (Moscow), 71, 1350-1356, https://doi.org/10.1134/s0006297906120108.

    Article  CAS  Google Scholar 

  25. Lapikov, I. A., Mogilenko, D. A., Dizhe, E. B., Ignatovich, I. A., Orlov, S. V., et al. (2008) Ap1-like cis-elements in the 5′-regulatory region of the human apolipoprotein A-I gene, Mol. Biol., 42, 295-305, https://doi.org/10.1134/S002689330802012X.

    Article  CAS  Google Scholar 

  26. Stahmann, N., Woods, A., Carling, D., and Heller, R. (2006) Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta, Mol. Cell. Biol., 26, 5933-5945, https://doi.org/10.1128/MCB.00383-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mogilenko, D. A., Shavva, V. S., Dizhe, E. B., Orlov, S. V., and Perevozchikov, A. P. (2010) PPARγ activates ABCA1 gene transcription but reduces the level of ABCA1 protein in HepG2 cells, Biochem. Biophys. Res. Commun., 402, 477-482, https://doi.org/10.1016/j.bbrc.2010.10.053.

    Article  CAS  PubMed  Google Scholar 

  28. Mogilenko, D. A., Kudriavtsev, I. V., Trulioff, A. S., Shavva, V. S., Dizhe, E. B., et al. (2012) Modified low density lipoprotein stimulates complement C3 expression and secretion via liver X receptor and Toll-like receptor 4 activation in human macrophages, J. Biol. Chem., 287, 5954-5968, https://doi.org/10.1074/jbc.M111.289322.

    Article  CAS  PubMed  Google Scholar 

  29. Tanyanskiy, D. A., Trulioff, A. S., Ageeva, E. V., Nikitin, A. A., Shavva, V. S., et al. (2021) The influence of adiponectin on production of apolipoproteins A-1 and E by human macrophages [in Russian], Mol. Biol. (Mosc.), 55, 697-704, https://doi.org/10.31857/S0026898421040121.

    Article  CAS  Google Scholar 

  30. Miller, R. A., Chu, Q., Le Lay, J., Scherer, P. E., Ahima, R. S., et al. (2011) Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling, J. Clin. Invest., 121, 2518-2528, https://doi.org/10.1172/JCI45942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shavva, V. S., Bogomolova, A. M., Efremov, A. M., Trofimov, A. N., Nikitin, A. A., et al. (2018) Insulin downregulates C3 gene expression in human HepG2 cells through activation of PPARγ, Eur. J. Cell Biol., 97, 204-215, https://doi.org/10.1016/j.ejcb.2018.03.001.

    Article  CAS  PubMed  Google Scholar 

  32. Leclerc, I., Lenzner, C., Gourdon, L., Vaulont, S., Kahn, A., et al. (2001) Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase, Diabetes, 50, 1515-1521, https://doi.org/10.2337/diabetes.50.7.1515.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The work was partially supported by the Russian Science Foundation (project no. 17-15-01326; experiments on the cell transfection with siRNAs and plasmids).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Institute of Experimental Medicine, 197376, St. Petersburg, Russia

    Dmitry A. Tanyanskiy, Vladimir S. Shavva, Ella B. Dizhe, Galina N. Oleinikova, Alexey V. Lizunov, Ekaterina V. Nekrasova, Denis A. Mogilenko, Ekaterina E. Larionova, Sergey V. Orlov & Alexander D. Denisenko

  2. Department of Fundamental Problems of Medicine and Medical Technologies, St. Petersburg State University, 199034, St. Petersburg, Russia

    Dmitry A. Tanyanskiy & Alexander D. Denisenko

  3. Department of Embryology, St. Petersburg State University, 199034, St. Petersburg, Russia

    Alexey V. Lizunov & Sergey V. Orlov

Authors
  1. Dmitry A. Tanyanskiy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vladimir S. Shavva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ella B. Dizhe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Galina N. Oleinikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexey V. Lizunov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ekaterina V. Nekrasova
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Denis A. Mogilenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ekaterina E. Larionova
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sergey V. Orlov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alexander D. Denisenko
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D. A. Tanyanskiy, S. V. Orlov, and A. D. Denisenko developed the concept and managed the study; D. A. Tanyanskiy, V. S. Shavva, E. B. Dizhe, G. N. Oleinikova, A. V. Lizunov, E. V. Nekrasova, D. A. Mogilenko, E. E. Larionova, and S. V. Orlov conducted the experiments; D. A. Tanyanskiy, V. S. Shavva, D. A. Mogilenko, S. V. Orlov, and A. D. Denisenko discussed the results of the study; D. A. Tanyanskiy wrote the manuscript; D. A. Tanyanskiy, S. V. Orlov, and A. D. Denisenko edited the text of the article.

Corresponding author

Correspondence to Dmitry A. Tanyanskiy.

Ethics declarations

The authors declare no conflict of interest. This article does not describe any studies involving humans or animals performed by any of the authors.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tanyanskiy, D.A., Shavva, V.S., Dizhe, E.B. et al. Adiponectin Stimulates Apolipoprotein A-1 Gene Expression in HepG2 Cells via AMPK, PPARα, and LXRs Signaling Mechanisms. Biochemistry Moscow 87, 1252–1259 (2022). https://doi.org/10.1134/S0006297922110049

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297922110049

Keywords

Search

Navigation