Skip to main content
Log in

Bile Acids as Metabolic Inducers of Hepatocyte Proliferation and Liver Regeneration

  • Review
  • Published:
Regenerative Engineering and Translational Medicine Aims and scope Submit manuscript

Abstract

Purpose

Liver regeneration is an orchestrated process that mainly comprises of the proliferation of the major liver cell types, that is, the hepatocytes and cholangiocytes, after liver injury (physical or chemical) in vivo. Although having a remarkable capacity to regenerate in vivo, hepatocytes are difficult to grow and maintain in culture as their viability and functions decline with time. The lack of a sufficient source of viable hepatocytes limits their clinical use for therapeutic applications.

Methods

In the current review, we have summarized the role of bile acids and their subsequent signaling pathways in liver regeneration in terms of both hepatocyte and cholangiocyte proliferation. We have also reviewed bile acid–based therapies in liver diseases.

Results

The expression of two major bile acid receptors, the farnesoid X receptor (FXR) and the Takeda G protein–coupled receptor (TGR5) in both the liver and the intestine immensely contribute to hepatocyte proliferation through varied mechanisms. Selective potent agonists of these two pathways are being synthesized for use as new therapies in several liver diseases.

Conclusion

FXR/TGR5 agonists hold immense potential to facilitate liver regeneration and ameliorate hepatic insufficiency in chronic liver diseases.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Ozaki M. Cellular and molecular mechanisms of liver regeneration: proliferation, growth, death and protection of hepatocytes. In Seminars in cell & developmental biology. 2020;100:62–73. 

  2. Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM, Hay T, et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol. 2015;17:971–83.

    Article  CAS  Google Scholar 

  3. Gadd VL, Aleksieva N, Forbes SJ. Epithelial plasticity during liver injury and regeneration: Cell Stem Cell. 2020;27:557–573.

  4. Forbes SJ, Newsome PN. Liver regeneration—mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol. 2016;13:473–85.

    Article  Google Scholar 

  5. Gilgenkrantz H, de l'Hortet AC. Understanding liver regeneration: from mechanisms to regenerative medicine. Am J Pathol. 2018;188:1316–27.

    Article  Google Scholar 

  6. Stolz DB, Mars WM, Petersen BE, Kim TH, Michalopoulos GK. Growth factor signal transduction immediately after two-thirds partial hepatectomy in the rat. Cancer Res. 1999;59:3954–60.

    CAS  Google Scholar 

  7. Mukhopadhyay S, Maitra U. Chemistry and biology of bile acids. Curr Sci. 2004 Dec;25:1666–83.

    Google Scholar 

  8. Chiang JY. Bile acid metabolism and signaling. Comprehensive Physiology. 2013;3:1191–212.

    Article  Google Scholar 

  9. Di Ciaula A, Garruti G, Baccetto RL, Molina-Molina E, Bonfrate L, Wang DQ, et al. Bile acid physiology. Ann Hepatol. 2018;16:4–14.

    Article  CAS  Google Scholar 

  10. Chiang JY, Ferrell JM. Bile acid biology, pathophysiology, and therapeutics. Clinical liver disease. 2020;15:91–4.

    Article  Google Scholar 

  11. Li T, Chiang JY. Regulation of bile acid and cholesterol metabolism by PPARs. PPAR research. 2009;2009:501739.

  12. Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014;11:55–67.

    Article  CAS  Google Scholar 

  13. Fiorucci S, Biagioli M, Zampella A, Distrutti E. Bile acids activated receptors regulate innate immunity. Front Immunol. 2018;9:1853.

    Article  CAS  Google Scholar 

  14. Honke N, Shaabani N, Hardt C, Krings C, Häussinger D, Lang PA, et al. Farnesoid X receptor in mice prevents severe liver immunopathology during lymphocytic choriomeningitis virus infection. Cell Physiol Biochem. 2017;41:323–38.

    Article  CAS  Google Scholar 

  15. Li J, Wilson A, Kuruba R, Zhang Q, Gao X, He F, et al. FXR-mediated regulation of eNOS expression in vascular endothelial cells. Cardiovasc Res. 2008;77:169–77.

    Article  CAS  Google Scholar 

  16. Fiorucci S, Distrutti E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med. 2015;21:702–14.

    Article  CAS  Google Scholar 

  17. Zhang Y, Hagedorn CH, Wang L. Role of nuclear receptor SHP in metabolism and cancer. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2011;1812:893–908.

    Article  CAS  Google Scholar 

  18. Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 2013;368:17–29.

    Article  CAS  Google Scholar 

  19. Duboc H, Taché Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis. 2014;46:302–12.

    Article  CAS  Google Scholar 

  20. Chiang JY, Ferrell JM. Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2020;318:G554–73.

    Article  Google Scholar 

  21. Jensen DD, Godfrey CB, Niklas C, Canals M, Kocan M, Poole DP, et al. The bile acid receptor TGR5 does not interact with β-arrestins or traffic to endosomes but transmits sustained signals from plasma membrane rafts. J Biol Chem. 2013;288:22942–60.

    Article  CAS  Google Scholar 

  22. Yasuda H, Hirata S, Inoue K, Mashima H, Ohnishi H, Yoshiba M. Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. Biochem Biophys Res Commun. 2007;354:154–9.

    Article  CAS  Google Scholar 

  23. Hong J, Behar J, Wands J, Resnick M, Wang LJ, DeLellis RA, et al. Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma. Gut. 2010;59:170–80.

    Article  CAS  Google Scholar 

  24. Reich M, Deutschmann K, Sommerfeld A, Klindt C, Kluge S, Kubitz R, et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut. 2016;65:487–501.

    Article  CAS  Google Scholar 

  25. Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5 as an emerging target in metabolism and inflammation. J Hepatol. 2011;54(6):1263–72.

    Article  CAS  Google Scholar 

  26. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10:167–77.

    Article  CAS  Google Scholar 

  27. Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Häussinger D. The membrane-bound bilacid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology. 2009 Sep;50(3):861–70.

    Article  CAS  Google Scholar 

  28. Hohenester S, Maillette de Buy Wenniger L, Paulusma CC, van Vliet SJ, Jefferson DM, Oude Elferink RP, et al. A biliary HCO3− umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology. 2012;55:173–83.

    Article  CAS  Google Scholar 

  29. Baghdasaryan A, Claudel T, Gumhold J, Silbert D, Adorini L, Roda A, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2−/−(Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO output. Hepatology. 2011;54:1303–12.

    Article  CAS  Google Scholar 

  30. Keitel V, Reinehr R, Gatsios P, Rupprecht C, Görg B, Selbach O, et al. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007;45:695–704.

    Article  CAS  Google Scholar 

  31. Keitel V, Donner M, Winandy S, Kubitz R, Häussinger D. Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun. 2008;372:78–84.

    Article  CAS  Google Scholar 

  32. Wang YD, Chen WD, Yu D, Forman BM, Huang W. The G-protein-coupled bile acid receptor, Gpbar1 (TGR5), negatively regulates hepatic inflammatory response through antagonizing nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) in mice. Hepatology. 2011;54:1421–32.

    Article  CAS  Google Scholar 

  33. Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5: a valuable metabolic target. Dig Dis. 2011;29:37–44.

    Article  CAS  Google Scholar 

  34. Csanaky IL, Aleksunes LM, Tanaka Y, Klaassen CD. Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2009;297:G419–33.

    Article  CAS  Google Scholar 

  35. Geier A, Wagner M, Dietrich CG, Trauner M. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. Biochimica et Biophysica Acta (BBA)-Molecular. Cell Res. 2007;1773:283–308.

    CAS  Google Scholar 

  36. Péan N, Doignon I, Garcin I, Besnard A, Julien B, Liu B, et al. The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. Hepatology. 2013;58:1451–60.

    Article  CAS  Google Scholar 

  37. Zhang L, Huang X, Meng Z, Dong B, Shiah S, Moore DD, et al. Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration. Mol Endocrinol. 2009;23:137–45.

    Article  CAS  Google Scholar 

  38. Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, et al. Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science. 2006;312:233–6.

    Article  CAS  Google Scholar 

  39. Meng Z, Wang Y, Wang L, Jin W, Liu N, Pan H, et al. FXR regulates liver repair after CCl4-induced toxic injury. Mol Endocrinol. 2010;24:886–97.

    Article  CAS  Google Scholar 

  40. de Haan L, van der Lely SJ, Warps AL, Hofsink Q, Olthof PB, de Keijzer MJ, et al. Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis. Journal of clinical and translational research. 2018;4:1.

    Google Scholar 

  41. García-Rodríguez JL, Barbier-Torres L, Fernández-Álvarez S, Gutiérrez-de Juan V, Monte MJ, Halilbasic E, et al. SIRT1 controls liver regeneration by regulating bile acid metabolism through farnesoid X receptor and mammalian target of rapamycin signaling. Hepatology. 2014;59:1972–83.

    Article  CAS  Google Scholar 

  42. Xie Y, Wang H, Cheng X, Wu Y, Cao L, Wu M, et al. Farnesoid X receptor activation promotes cell proliferation via PDK4-controlled metabolic reprogramming. Sci Rep. 2016;6:1–1.

    CAS  Google Scholar 

  43. Uriarte I, Fernandez-Barrena MG, Monte MJ, Latasa MU, Chang HC, Carotti S, et al. Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut. 2013;62:899–910.

    Article  CAS  Google Scholar 

  44. Kong B, Huang J, Zhu Y, Li G, Williams J, Shen S, et al. Fibroblast growth factor 15 deficiency impairs liver regeneration in mice. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2014;306:G893–902.

    Article  CAS  Google Scholar 

  45. Fan M, Wang X, Xu G, Yan Q, Huang W. Bile acid signaling and liver regeneration. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms. 2015;1849:196–200.

    Article  CAS  Google Scholar 

  46. Bhushan B, Borude P, Edwards G, Walesky C, Cleveland J, Li F, et al. Role of bile acids in liver injury and regeneration following acetaminophen overdose. Am J Pathol. 2013;183:1518–26.

    Article  CAS  Google Scholar 

  47. Fernández-Barrena MG, Monte MJ, Latasa MU, Uriarte I, Vicente E, Chang HC, et al. Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice. J Hepatol. 2012;56:367–73.

    Article  CAS  Google Scholar 

  48. Naugler WE, Tarlow BD, Fedorov LM, Taylor M, Pelz C, Li B, et al. Fibroblast growth factor signaling controls liver size in mice with humanized livers. Gastroenterology. 2015;149:728–40.

    Article  CAS  Google Scholar 

  49. Otao R, Beppu T, Isiko T, Mima K, Okabe H, Hayashi H, et al. External biliary drainage and liver regeneration after major hepatectomy. Br J Surg. 2012;99:1569–74.

    Article  CAS  Google Scholar 

  50. Alison MR, Lin WR. Diverse routes to liver regeneration. J Pathol. 2016;238:371–4.

    Article  Google Scholar 

  51. Hendrick SM, Mroz MS, Greene CM, Keely SJ, Harvey BJ. Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl− channels in Calu-3 airway epithelial cells. Am J Phys Lung Cell Mol Phys. 2014;307:L407–18.

    CAS  Google Scholar 

  52. Guo C, Chen WD, Wang YD. TGR5, not only a metabolic regulator. Front Physiol. 2016;7:646.

    Article  Google Scholar 

  53. Kida T, Tsubosaka Y, Hori M, Ozaki H, Murata T. Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33:1663–9.

    Article  CAS  Google Scholar 

  54. Kaur S, Tripathi DM, Venugopal JR, Ramakrishna S. Advances in biomaterials for hepatic tissue engineering. Current Opinion in Biomedical Engineering. 2020;13:A1–6.

    Article  Google Scholar 

  55. Martinez-Diez MC, Serrano MA, Monte MJ, Marin JJ. Comparison of the effects of bile acids on cell viability and DNA synthesis by rat hepatocytes in primary culture. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2000;1500:153–60.

    Article  CAS  Google Scholar 

  56. Sun S, Zhao B, Qi M, Yao Y, Xu L, Ji R, et al. TUDCA Ameliorates liver Injury via activation of SIRT1-FXR Signaling in a Rat hemorrhagic shock model. Shock. 2020;53:217–22.

    Article  CAS  Google Scholar 

  57. Sawitza I, Kordes C, Götze S, Herebian D, Häussinger D. Bile acids induce hepatic differentiation of mesenchymal stem cells. Sci Rep. 2015;5:1–5.

    Article  CAS  Google Scholar 

  58. Bose S, Robertson SF, Bandyopadhyay A. Surface modification of biomaterials and biomedical devices using additive manufacturing. Acta Biomater. 2018;66:6–22.

    Article  CAS  Google Scholar 

  59. Haga S, Yimin OM. Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver, especially with steatosis. BMC Gastroenterol. 2017;17:9.

    Article  CAS  Google Scholar 

  60. Wigger L, Casals-Casas C, Baruchet M, Trang KB, Pradervand S, Naldi A, et al. System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLoS One. 2019;14:e0220894.

    Article  CAS  Google Scholar 

  61. Vaquero J, Briz O, Herraez E, Muntané J, Marin JJ. Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. Biochim Biophys Acta. 1833;2013:2212–9.

    Google Scholar 

  62. Dash A, Figler RA, Blackman BR, Marukian S, Collado MS, Lawson MJ, et al. Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol in Vitro. 2017;39:93–103.

    Article  CAS  Google Scholar 

  63. Goto T, Itoh M, Suganami T, Kanai S, Shirakawa I, Sakai T, et al. Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis. Sci Rep. 2018;8:8157.

    Article  CAS  Google Scholar 

  64. Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 2011;14:747–57.

    Article  CAS  Google Scholar 

  65. Tabibian JH, Masyuk AI, Masyuk TV, O'Hara SP, LaRusso NF. Physiology of cholangiocytes. Comprehensive Physiology. 2013 Jan;3(1):541–65.

    Article  Google Scholar 

  66. Kaur S, Siddiqui H, Bhat MH. Hepatic progenitor cells in action: liver regeneration or fibrosis? Am J Pathol. 2015;185:2342–50.

    Article  CAS  Google Scholar 

  67. Raven A, Lu WY, Man TY, Ferreira-Gonzalez S, O’Duibhir E, Dwyer BJ, et al. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature. 2017;547:350–4.

    Article  CAS  Google Scholar 

  68. Alpini GI, Glaser SH, Robertson WI, Phinizy JL, Rodgers RE, Caligiuri AL, et al. Bile acids stimulate proliferative and secretory events in large but not small cholangiocytes. American Journal of Physiology-Gastrointestinal and Liver Physiology. 1997;273:G518–29.

    Article  CAS  Google Scholar 

  69. Alpini G, Glaser SS, Ueno Y, Rodgers R, Phinizy JL, Francis H, et al. Bile acid feeding induces cholangiocyte proliferation and secretion: Evidence for bile acid–regulated ductal secretion. Gastroenterology. 1999;116:179–86.

    Article  CAS  Google Scholar 

  70. Lu L, Finegold MJ, Johnson RL. Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Exp Mol Med. 2018;50:e423.

    Article  Google Scholar 

  71. Verboven E, Moya IM, Sansores-Garcia L, Xie J, Hillen H, Kowalczyk W, et al. Regeneration defects in yap and taz mutant mouse livers are caused by bile duct disruption and cholestasis. Gastroenterology. 2021;160:847–62.

    Article  CAS  Google Scholar 

  72. Pepe-Mooney BJ, Dill MT, Alemany A, Ordovas-Montanes J, Matsushita Y, Rao A, et al. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell. 2019;25:23–38.

    Article  CAS  Google Scholar 

  73. Anakk S, Bhosale M, Schmidt VA, Johnson RL, Finegold MJ, Moore DD. Bile acids activate YAP to promote liver carcinogenesis. Cell Rep. 2013;5:1060–9.

    Article  CAS  Google Scholar 

Download references

Funding

The work was supported by the SRF project (45/5/2020-PHY/BMS) by the Indian Council of Medical Research, India.

Author information

Authors and Affiliations

Authors

Contributions

IK and RT drafted the manuscript and the figures, DMT edited the figures, VGM and SR provided valuable inputs, and SK edited and finalized the manuscript and the figures. All authors approved the manuscript.

Corresponding author

Correspondence to Savneet Kaur.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kaur, I., Tiwari, R., Naidu, V. et al. Bile Acids as Metabolic Inducers of Hepatocyte Proliferation and Liver Regeneration. Regen. Eng. Transl. Med. 8, 200–209 (2022). https://doi.org/10.1007/s40883-021-00221-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40883-021-00221-2

Keywords

Navigation