Skip to main content
SpringerLink
Log in

Low Molecular Pectin Inhibited the Lipid Accumulation by Upregulation of METTL7B

  • Original Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Inhibition of lipid accumulation is the key step to prevent nonalcoholic fatty liver (NAFL) progressing to nonalcoholic steatohepatitis. We aimed to study the effect of low-molecular-weight citrus pectin (LCP) against lipid accumulation and the underlying mechanism. Oleic acid (OA)-induced lipid deposition in HepG2 cells was applied to mimic in vitro model of lipid accumulation. Oil Red O (ORO) stain result showed lipid accumulation was significantly reduced, and levels of adipose triglyceride lipase (ATGL) and carnitine palmitoyltransferase-1 (CPT-1), involved in triacylglycerol catabolism and fatty acid β-oxidation, detected by RT-qPCR were increased after OA-stimulated HepG2 cells treated with LCP. RNA sequencing analysis identified 740 differentially expressed genes (DEGs) in OA-stimulated HepG2 cells treated with the LCP group (OA+LCP group), and bioinformatics analysis indicated that some DEGs were enriched in lipid metabolism-related processes and pathways. The expression of the top 8 known DEGs in the OA+LCP group was then verified by RT-qPCR, which showed that fold change (abs) of METTL7B was the highest among the 8 candidates. In addition, overexpression of METTL7B in HepG2 cells significantly inhibited the lipid accumulation and enhanced levels of ATGL and CPT-1. In conclusion, LCP inhibited lipid accumulation through the upregulation of METTL7B, and further enhancement of ATGL and CPT-1 levels. LCP is expected to develop as a promising agent to ameliorate fat accumulation in NAFL.

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

References

  1. Sheka, A. C., Adeyi, O., Thompson, J., Hameed, B., Crawford, P. A., & Ikramuddin, S. (2020). Nonalcoholic steatohepatitis: a review. JAMA, 323(12), 1175–1183.

    Article  CAS  Google Scholar 

  2. Dietrich, P., & Hellerbrand, C. (2014). Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Practice & Research. Clinical Gastroenterology, 28(4), 637–653.

    Article  CAS  Google Scholar 

  3. Dibba, P., Li, A., Perumpail, B., John, N., Sallam, S., Shah, N., et al. (2018). Emerging therapeutic targets and experimental drugs for the treatment of NAFLD. Diseases, 6(3), 1–15.

    Article  Google Scholar 

  4. Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J., Boursier, J., Mathurin, P., Bugianesi, E., Mazzella, G., Olveira, A., Cortez-Pinto, H., Graupera, I., Orr, D., Gluud, L. L., Dufour, J. F., Shapiro, D., Campagna, J., Zaru, L., MacConell, L., Shringarpure, R., Harrison, S., Sanyal, A. J., Abdelmalek, M., Abrams, G., Aguilar, H., Ahmed, A., Aigner, E., Aithal, G., Ala, A., Alazawi, W., Albillos, A., Allison, M., al-Shamma, S., Andrade, R., Andreone, P., Angelico, M., Ankoma-Sey, V., Anstee, Q., Anty, R., Araya, V., Arenas Ruiz, J. I., Arkkila, P., Arora, M., Asselah, T., Au, J., Ayonrinde, O., Bailey, R. J., Balakrishnan, M., Bambha, K., Bansal, M., Barritt, S., Bate, J., Beato, J., Beckebaum, S., Behari, J., Bellot, P., Ben Ari, Z., Bennett, M., Berenguer, M., Beretta-Piccoli, B. T., Berg, T., Bonacini, M., Bonet, L., Borg, B., Bourliere, M., Boursier, J., Bowman, W., Bradley, D., Brankovic, M., Braun, M., Bronowicki, J. P., Bruno, S., Bugianesi, E., Cai, C., Calleja Panero, J. L., Carey, E., Carmiel, M., Carrión, J. A., Cave, M., Chagas, C., Chami, T., Chang, A., Coates, A., Cobbold, J., Corey, K., Corless, L., Cortez-Pinto, H., Crespo, J., Cruz Pereira, O., de Ledinghen, V., deLemos, A., Diago, M., Dufour, J. F., Dugalic, P., Dunn, W., Elkhashab, M., Epstein, M., Escudero-Garcia, M. D., Etzion, O., Evans, L., Falcone, R., Fernandez, C., Ferreira, J., Fink, S., Finnegan, K., Firpi-Morell, R., Floreani, A., Fontanges, T., Ford, R., Forrest, E., Fowell, A., Fracanzani, A. L., Francque, S., Freilich, B., Frias, J., Fuchs, M., Fuentes, J., Galambos, M., Gallegos, J., Geerts, A., Geier, A., George, J., Ghali, M., Ghalib, R., Gholam, P., Gines, P., Gitlin, N., Gluud, L. L., Goeser, T., Goff, J., Gordon, S., Gordon, F., Goria, O., Greer, S., Grigorian, A., Gronbaek, H., Guillaume, M., Gunaratnam, N., Halegoua-de Marzio, D., Hameed, B., Hametner, S., Hamilton, J., Harrison, S., Hartleb, M., Hassanein, T., Häussinger, D., Hellstern, P., Herring, R., Heurich, E., Hezode, C., Hinrichsen, H., Holland Fischer, P., Horsmans, Y., Huang, J., Jakiche, A., Jeffers, L., Jones, B., Jorge, R., Jorquera, F., Kahraman, A., Kaita, K., Karyotakis, N., Kayali, Z., Kechagias, S., Kepczyk, T., Khalili, M., Khallafi, H., Kluwe, J., Knapple, W., Kohli, A., Korenblat, K., Kowdley, K., Krag, A., Krause, R., Kremer, A., Krok, K., Krstic, M., Kugelmas, M., Kumar, S., Labarriere, D., Lai, M., Lampertico, P., Lawitz, E., Lee, A., Leroy, V., Lidofsky, S., Lim, T. H., Lim, J., Lipkis, D., Little, E., Lonardo, A., Long, M., Loomba, R., Lurie, Y., Macedo, G., Makara, M., Maliakkal, B., Manns, M., Manousou, P., Mantry, P., Marchesini, G., Marinho, C., Marotta, P., Marschall, H. U., Mathurin, P., Mayo, M., Mazzella, G., McCullen, M., McLaughlin, W., Merriman, R., Modi, A., Molina, E., Montano-Loza, A., Monteverde, C., Moreea, S., Moreno, C., Morisco, F., Mubarak, A., Muellhaupt, B., Mukherjee, S., Müller, T., Nagorni, A., Naik, J., Neff, G., Nevah, M., Newsome, P., Nguyen-Khac, E., Noureddin, M., Oben, J., Olveira, A., Orlent, H., Orr, D., Orr, J., Ortiz-Lasanta, G., Ozenne, V., Pandya, P., Paredes, A., Park, J., Patel, J., Patel, K., Uta, M., Patton, H., Peck-Radosavljevic, M., Petta, S., Pianko, S., Piekarska, A., Pimstone, N., Pockros, P., Pol, S., Porayko, M., Poulos, J., Pound, D., Pouzar, J., Presa Ramos, J., Pyrsopoulos, N., Rafiq, N., Muller, K., Ramji, A., Ratziu, V., Ravinuthala, R., Reddy, C., Reddy K G, G., Reddy K R, K. R., Regenstein, F., Reindollar, R., Riera, A., Rinella, M., Rivera Acosta, J., Robaeys, G., Roberts, S., Rodriguez-Perez, F., Romero-Gomez, M., Rubin, R., Rumi, M., Rushbrook, S., Rust, C., Ryan, M., Safadi, R., Said, A., Salminen, K., Samuel, D., Santoro, J., Sanyal, A., Sarkar, S., Schaeffer, C., Schattenberg, J., Schiefke, I., Schiff, E., Schmidt, W., Schneider, J., Schouten, J., Schultz, M., Sebastiani, G., Semela, D., Sepe, T., Sheikh, A., Sheikh, M., Sheridan, D., Sherman, K., Shibolet, O., Shiffman, M., Siddique, A., Sieberhagen, C., Sigal, S., Sikorska, K., Simon, K., Sinclair, M., Skoien, R., Solis, J., Sood, S., Souder, B., Spivey, J., Stal, P., Stinton, L., Strasser, S., Svorcan, P., Szabo, G., Talal, A., Tam, E., Tetri, B., Thuluvath, P., Tobias, H., Tomasiewicz, K., Torres, D., Trauner, M., Trautwein, C., Trotter, J., Tsochatzis, E., Unitt, E., Vargas, V., Varkonyi, I., Veitsman, E., Vespasiani Gentilucci, U., Victor, D., Vierling, J., Vincent, C., Vincze, A., von der Ohe, M., von Roenn, N., Vuppalanchi, R., Waters, M., Watt, K., Weltman, M., Wieland, A., Wiener, G., Williams A, A., Williams J, J., Wilson, J., Yataco, M., Yoshida, E., Younes, Z., Yuan, L., Zivony, A., Zogg, D., Zoller, H., Zoulim, F., Zuckerman, E., & Zuin, M. (2019). Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet, 394(10215), 2184–2196.

    Article  CAS  Google Scholar 

  5. Harrison, S. A., Bashir, M. R., Guy, C. D., Zhou, R., Moylan, C. A., Frias, J. P., Alkhouri, N., Bansal, M. B., Baum, S., Neuschwander-Tetri, B. A., Taub, R., & Moussa, S. E. (2019). Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet, 394(10213), 2012–2024.

    Article  CAS  Google Scholar 

  6. Chen, Y., Feng, R., Yang, X., Dai, J., Huang, M., Ji, X., Li, Y., Okekunle, A. P., Gao, G., Onwuka, J. U., Pang, X., Wang, C., Li, C., Li, Y., & Sun, C. (2019). Yogurt improves insulin resistance and liver fat in obese women with nonalcoholic fatty liver disease and metabolic syndrome: a randomized controlled trial. The American Journal of Clinical Nutrition, 109(6), 1611–1619.

    Article  Google Scholar 

  7. Ciriminna, R., Fidalgo, A., Delisi, R., Tamburino, A., Carnaroglio, D., Cravotto, G., Ilharco, L. M., & Pagliaro, M. (2017). Controlling the degree of esterification of citrus pectin for demanding applications by selection of the source. ACS Omega, 2(11), 7991–7995.

    Article  CAS  Google Scholar 

  8. Delphi, L., & Sepehri, H. (2016). Apple pectin: a natural source for cancer suppression in 4T1 breast cancer cells in vitro and express p53 in mouse bearing 4T1 cancer tumors, in vivo. Biomedicine & Pharmacotherapy, 84, 637–644.

    Article  CAS  Google Scholar 

  9. Wang, S., Li, P., Lu, S. M., & Ling, Z. Q. (2016). Chemoprevention of low-molecular-weight citrus pectin (LCP) in gastrointestinal cancer cells. International Journal of Biological Sciences, 12(6), 746–756.

    Article  CAS  Google Scholar 

  10. Eliaz, I., & Raz, A. (2019). Pleiotropic effects of modified citrus pectin. Nutrients, 11(11), 1–18.

    Article  Google Scholar 

  11. Abu-Elsaad, N. M., & Elkashef, W. F. (2016). Modified citrus pectin stops progression of liver fibrosis by inhibiting galectin-3 and inducing apoptosis of stellate cells. Canadian Journal of Physiology and Pharmacology, 94(5), 554–562.

    Article  CAS  Google Scholar 

  12. Martinez-Martinez, E., Calvier, L., Rossignol, P., Rousseau, E., Fernandez-Celis, A., Jurado-Lopez, R., Laville, M., Cachofeiro, V., & Lopez-Andres, N. (2016). Galectin-3 inhibition prevents adipose tissue remodelling in obesity. International Journal of Obesity, 40(6), 1034–1038.

    Article  CAS  Google Scholar 

  13. Marin-Royo, G., et al. (2018). Inhibition of galectin-3 ameliorates the consequences of cardiac lipotoxicity in a rat model of diet-induced obesity. Disease Models & Mechanisms, 11(2), dmm032086.

    Article  Google Scholar 

  14. Eliaz, I., Hotchkiss, A. T., Fishman, M. L., & Rode, D. (2006). The effect of modified citrus pectin on urinary excretion of toxic elements. Phytotherapy Research, 20(10), 859–864.

    Article  CAS  Google Scholar 

  15. Hong, Y., Choi, S. I., Hong, E., & Kim, G. H. (2020). Psoralea corylifolia L. extract ameliorates nonalcoholic fatty liver disease in free-fatty-acid-incubated HEPG2 cells and in high-fat diet-fed mice. Journal of Food Science, 85(7), 2216–2226.

    Article  CAS  Google Scholar 

  16. Guo, L., Kang, J. S., Park, Y. H., Je, B. I., Lee, Y. J., Kang, N. J., Park, S. Y., Hwang, D. Y., & Choi, Y. W. (2020). S-petasin inhibits lipid accumulation in oleic acid-induced HepG2 cells through activation of the AMPK signaling pathway. Food & Function, 11(6), 5664–5673.

    Article  CAS  Google Scholar 

  17. Ren, G., Guo, J. H., Qian, Y. Z., Kong, W. J., & Jiang, J. D. (2020). Berberine improves glucose and lipid metabolism in HepG2 cells through AMPKalpha1 activation. Frontiers in Pharmacology, 11, 647.

    Article  CAS  Google Scholar 

  18. Yang, J., et al. (2013). Glucagon-like peptide 1 regulates adipogenesis in 3T3-L1 preadipocytes. International Journal of Molecular Medicine, 31(6), 1429–1435.

    Article  CAS  Google Scholar 

  19. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods, 25(4), 402–408.

    Article  CAS  Google Scholar 

  20. European Association for the Study of the, L., European Association for the Study of, D., & European Association for the Study of, O. (2016). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Obesity Facts, 9(2), 65–90.

    Article  Google Scholar 

  21. Chalasani, N., Younossi, Z., Lavine, J. E., Diehl, A. M., Brunt, E. M., Cusi, K., Charlton, M., & Sanyal, A. J. (2012). The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology, 55(6), 2005–2023.

    Article  Google Scholar 

  22. Liu, Y. T., Lai, Y. H., Lin, H. H., & Chen, J. H. (2019). Lotus seedpod extracts reduced lipid accumulation and lipotoxicity in hepatocytes. Nutrients, 11(12), 1–15.

    Google Scholar 

  23. Zhang, J., Zhang, S. D., Wang, P., Guo, N., Wang, W., Yao, L. P., Yang, Q., Efferth, T., Jiao, J., & Fu, Y. J. (2019). Pinolenic acid ameliorates oleic acid-induced lipogenesis and oxidative stress via AMPK/SIRT1 signaling pathway in HepG2 cells. European Journal of Pharmacology, 861, 172618.

    Article  CAS  Google Scholar 

  24. Shen, B., Feng, H., Cheng, J., Li, Z., Jin, M., Zhao, L., Wang, Q., Qin, H., & Liu, G. (2020). Geniposide alleviates non-alcohol fatty liver disease via regulating Nrf2/AMPK/mTOR signalling pathways. Journal of Cellular and Molecular Medicine, 24(9), 5097–5108.

    Article  CAS  Google Scholar 

  25. Mun, J., et al. (2019). Water extract of Curcuma longa L. ameliorates non-alcoholic fatty liver disease. Nutrients, 11(10), 1–13.

  26. Zimmermann, R., Strauss, J. G., Haemmerle, G., Schoiswohl, G., Birner-Gruenberger, R., Riederer, M., Lass, A., Neuberger, G., Eisenhaber, F., Hermetter, A., & Zechner, R. (2004). Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science, 306(5700), 1383–1386.

    Article  CAS  Google Scholar 

  27. Wang, Y., Chen, Y., Guan, L., Zhang, H., Huang, Y., Johnson, C. H., Wu, Z., Gonzalez, F. J., Yu, A., Huang, P., Wang, Y., Yang, S., Chen, P., Fan, X., Huang, M., & Bi, H. (2018). Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming. Cell Death and Differentiation, 25(4), 735–748.

    Article  CAS  Google Scholar 

  28. Pramfalk, C., et al. (2020). Generation of new hepatocyte-like in vitro models better resembling human lipid metabolism. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1865(6), 158659.

    Article  CAS  Google Scholar 

  29. Sodhi, S. S., Ghosh, M., Song, K. D., Sharma, N., Kim, J. H., Kim, N. E., Lee, S. J., Kang, C. W., Oh, S. J., & Jeong, D. K. (2014). An approach to identify SNPs in the gene encoding acetyl-CoA acetyltransferase-2 (ACAT-2) and their proposed role in metabolic processes in pig. PLoS One, 9(7), e102432.

    Article  Google Scholar 

  30. Korner, A., et al. (2019). Inhibition of delta24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution. Proceedings of the National Academy of Sciences of the United States of America, 116(41), 20623–20634.

    Article  Google Scholar 

  31. Wu, X., Sang, L., & Gong, Y. (2018). N6-methyladenine RNA modification and cancers. American Journal of Cancer Research, 8(10), 1957–1966.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, M., & Wong, C. M. (2020). The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis. Molecular Cancer, 19(1), 44.

    Article  CAS  Google Scholar 

  33. Zhong, H., Tang, H. F., & Kai, Y. (2020). N6-methyladenine RNA modification (m6A): an emerging regulator of metabolic diseases. Current Drug Targets, 21(11), 1056–1067.

    Article  CAS  Google Scholar 

  34. Luo, Z., Zhang, Z., Tai, L., Zhang, L., Sun, Z., & Zhou, L. (2019). Comprehensive analysis of differences of N(6)-methyladenosine RNA methylomes between high-fat-fed and normal mouse livers. Epigenomics, 11(11), 1267–1282.

    Article  CAS  Google Scholar 

  35. Lu, N., Li, X., Yu, J., Li, Y., Wang, C., Zhang, L., Wang, T., & Zhong, X. (2018). Curcumin attenuates lipopolysaccharide-induced hepatic lipid metabolism disorder by modification of m(6) A RNA methylation in piglets. Lipids, 53(1), 53–63.

    Article  Google Scholar 

  36. Zhong, X., Yu, J., Frazier, K., Weng, X., Li, Y., Cham, C. M., Dolan, K., Zhu, X., Hubert, N., Tao, Y., Lin, F., Martinez-Guryn, K., Huang, Y., Wang, T., Liu, J., He, C., Chang, E. B., & Leone, V. (2018). Circadian clock regulation of hepatic lipid metabolism by modulation of m(6) A mRNA methylation. Cell Reports, 25(7), 1816–1828 e1814.

    Article  CAS  Google Scholar 

  37. Kang, H., Zhang, Z., Yu, L., Li, Y., Liang, M., & Zhou, L. (2018). FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation. Journal of Cellular Biochemistry, 119(7), 5676–5685.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Research Project of Shanghai Minhang Science and Technology Committee (2018MHZ074, 2019MHZ069) and Special Construction Project of Integrated Traditional Chinese and Western Medicine in Shanghai General Hospital (ZHYY-ZXYJHZX-201622).

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Shanghai Fifth People’s Hospital, Fudan University, No. 128 Ruili Road, Shanghai, 200240, China

    Xiaojin Yang, Yinghua Yuan & Desheng Xie

Authors
  1. Xiaojin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yinghua Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Desheng Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yinghua Yuan.

Ethics declarations

Conflict of Interest

The authors declare no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Fig. S1

Top 30 KEGG pathway enrichment. The size of circle indicates the number of DEGs; the color indicates the value of P. DEGs, differentially expressed genes. (JPG 351 kb)

ESM 1

(XLS 20 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, X., Yuan, Y. & Xie, D. Low Molecular Pectin Inhibited the Lipid Accumulation by Upregulation of METTL7B. Appl Biochem Biotechnol 193, 1469–1481 (2021). https://doi.org/10.1007/s12010-021-03486-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-021-03486-z

Keywords

Search

Navigation