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Semin Liver Dis 2023; 43(01): 024-030
DOI: 10.1055/a-2015-1359
Review Article

Growth Hormone Signaling in Liver Diseases: Therapeutic Potentials and Controversies

Madisyn Oxley
1   Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
,
Heather Francis
1   Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
2   Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
,
Keisaku Sato
1   Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
› Author Affiliations Funding This work was supported by the Indiana University Health – Indiana University School of Medicine Strategic Research Initiative, the Career Scientist Award (IK6BX005226), and the VA Merit award (1I01BX003031) to H.F. from the United States Department of Veteran's Affairs, Biomedical Laboratory Research and Development Service, and NIH grants AA030107, DK108959, and DK119421 (H.F.). Portions of these studies were supported by resources at Richard L. Roudebush VA Medical Center, Indianapolis, IN. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.
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Abstract

Growth hormone (GH) and downstream insulin-like growth factor 1 (IGF1) signaling mediate growth and metabolism. GH deficiency causes short stature or dwarfism, and excess GH causes acromegaly. Although the association of GH/IGF1 signaling with liver diseases has been suggested previously, current studies are controversial and the functional roles of GH/IGF1 signaling are still undefined. GH supplementation therapy showed promising therapeutic effects in some patients, such as non-alcoholic fatty liver disease, but inhibition of GH signaling may be beneficial for other liver diseases, such as hepatocellular carcinoma. The functional roles of GH/IGF1 signaling and the effects of agonists/antagonists targeting this signaling may differ depending on the liver injury or animal models. This review summarizes current controversial studies of GH/IGF1 signaling in liver diseases and discusses therapeutic potentials of GH therapy.

Keywords

growth hormone - liver regeneration - lipid metabolism - liver fibrosis - hepatic tumorigenesis


Publication History

Accepted Manuscript online:
18 January 2023

Article published online:
10 February 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Ranke MB, Wit JM. Growth hormone - past, present and future. Nat Rev Endocrinol 2018; 14 (05) 285-300
    CrossrefPubMedGoogle Scholar
  • 2 Ayuk J, Sheppard MC. Growth hormone and its disorders. Postgrad Med J 2006; 82 (963) 24-30
    CrossrefPubMedGoogle Scholar
  • 3 Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. Mol Pathol 2001; 54 (05) 311-316
    CrossrefPubMedGoogle Scholar
  • 4 Dehkhoda F, Lee CMM, Medina J, Brooks AJ. The growth hormone receptor: Mechanism of receptor activation, cell signaling, and physiological aspects. Front Endocrinol (Lausanne) 2018; 9: 35
    CrossrefPubMedGoogle Scholar
  • 5 Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nat Rev Endocrinol 2013; 9 (06) 366-376
    CrossrefPubMedGoogle Scholar
  • 6 Colon G, Saccon T, Schneider A. et al. The enigmatic role of growth hormone in age-related diseases, cognition, and longevity. Geroscience 2019; 41 (06) 759-774
    CrossrefPubMedGoogle Scholar
  • 7 Bartke A, Brown-Borg H, Kinney B. et al. Growth hormone and aging. J Am Aging Assoc 2000; 23 (04) 219-225
    PubMedGoogle Scholar
  • 8 Sonntag WE, Csiszar A, deCabo R, Ferrucci L, Ungvari Z. Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies. J Gerontol A Biol Sci Med Sci 2012; 67 (06) 587-598
    CrossrefPubMedGoogle Scholar
  • 9 Takahashi Y. The role of growth hormone and insulin-like growth factor-I in the liver. Int J Mol Sci 2017; 18 (07) 18
    CrossrefPubMedGoogle Scholar
  • 10 Møller N, Jørgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev 2009; 30 (02) 152-177
    CrossrefPubMedGoogle Scholar
  • 11 Attanasio AF, Mo D, Erfurth EM. et al; International Hypopituitary Control Complications Study Advisory Board. Prevalence of metabolic syndrome in adult hypopituitary growth hormone (GH)-deficient patients before and after GH replacement. J Clin Endocrinol Metab 2010; 95 (01) 74-81
    CrossrefPubMedGoogle Scholar
  • 12 Xu L, Xu C, Yu C. et al. Association between serum growth hormone levels and nonalcoholic fatty liver disease: a cross-sectional study. PLoS One 2012; 7 (08) e44136
    CrossrefPubMedGoogle Scholar
  • 13 Scacchi M, Pincelli AI, Cavagnini F. Growth hormone in obesity. Int J Obes Relat Metab Disord 1999; 23 (03) 260-271
    CrossrefPubMedGoogle Scholar
  • 14 Liang S, Cheng X, Hu Y, Song R, Li G. Insulin-like growth factor 1 and metabolic parameters are associated with nonalcoholic fatty liver disease in obese children and adolescents. Acta Paediatr 2017; 106 (02) 298-303
    CrossrefPubMedGoogle Scholar
  • 15 Isojima T, Shimatsu A, Yokoya S. et al. Standardized centile curves and reference intervals of serum insulin-like growth factor-I (IGF-I) levels in a normal Japanese population using the LMS method. Endocr J 2012; 59 (09) 771-780
    CrossrefPubMedGoogle Scholar
  • 16 Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000; 106 (04) 473-481
    CrossrefPubMedGoogle Scholar
  • 17 Kuang J, Zhang L, Xu Y, Xue J, Liang S, Xiao J. Reduced insulin-like growth factor 1 is associated with insulin resistance in obese prepubertal boys. BioMed Res Int 2021; 2021: 6680316
    CrossrefPubMedGoogle Scholar
  • 18 Xue J, Liang S, Ma J, Xiao Y. Effect of growth hormone therapy on liver enzyme and other cardiometabolic risk factors in boys with obesity and nonalcoholic fatty liver disease. BMC Endocr Disord 2022; 22 (01) 49
    CrossrefPubMedGoogle Scholar
  • 19 Reeder SB, Sirlin CB. Quantification of liver fat with magnetic resonance imaging. Magn Reson Imaging Clin N Am 2010; 18 (03) 337-357 , ix
    CrossrefPubMedGoogle Scholar
  • 20 Pan CS, Weiss JJ, Fourman LT. et al. Effect of recombinant human growth hormone on liver fat content in young adults with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf) 2021; 94 (02) 183-192
    CrossrefPubMedGoogle Scholar
  • 21 Molitch ME, Clemmons DR, Malozowski S. et al; Endocrine Society's Clinical Guidelines Subcommittee. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2006; 91 (05) 1621-1634
    CrossrefPubMedGoogle Scholar
  • 22 Nishizawa H, Iguchi G, Murawaki A. et al. Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. Eur J Endocrinol 2012; 167 (01) 67-74
    CrossrefPubMedGoogle Scholar
  • 23 Jang HS, Kim K, Lee MR, Kim SH, Choi JH, Park MJ. Treatment of growth hormone attenuates hepatic steatosis in hyperlipidemic mice via downregulation of hepatic CD36 expression. Anim Cells Syst 2020; 24 (03) 151-159
    CrossrefPubMedGoogle Scholar
  • 24 O'Rourke JM, Sagar VM, Shah T, Shetty S. Carcinogenesis on the background of liver fibrosis: implications for the management of hepatocellular cancer. World J Gastroenterol 2018; 24 (39) 4436-4447
    CrossrefPubMedGoogle Scholar
  • 25 Hribal ML, Procopio T, Petta S. et al. Insulin-like growth factor-I, inflammatory proteins, and fibrosis in subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2013; 98 (02) E304-E308
    CrossrefPubMedGoogle Scholar
  • 26 Chishima S, Kogiso T, Matsushita N, Hashimoto E, Tokushige K. The relationship between the growth hormone/insulin-like growth factor system and the histological features of nonalcoholic fatty liver disease. Intern Med 2017; 56 (05) 473-480
    CrossrefPubMedGoogle Scholar
  • 27 Alisi A, Pampanini V, De Stefanis C. et al. Expression of insulin-like growth factor I and its receptor in the liver of children with biopsy-proven NAFLD. PLoS One 2018; 13 (07) e0201566
    CrossrefPubMedGoogle Scholar
  • 28 Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18 (03) 151-166
    CrossrefPubMedGoogle Scholar
  • 29 Acharya P, Chouhan K, Weiskirchen S, Weiskirchen R. Cellular mechanisms of liver fibrosis. Front Pharmacol 2021; 12: 671640
    CrossrefPubMedGoogle Scholar
  • 30 Svegliati-Baroni G, Ridolfi F, Di Sario A. et al. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology 1999; 29 (06) 1743-1751
    CrossrefPubMedGoogle Scholar
  • 31 Sanz S, Pucilowska JB, Liu S. et al. Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury. Gut 2005; 54 (01) 134-141
    CrossrefPubMedGoogle Scholar
  • 32 Nishizawa H, Iguchi G, Fukuoka H. et al. IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner. Sci Rep 2016; 6: 34605
    CrossrefPubMedGoogle Scholar
  • 33 Saraceni C, Birk J. A review of hepatitis B virus and hepatitis C virus immunopathogenesis. J Clin Transl Hepatol 2021; 9 (03) 409-418
    PubMedGoogle Scholar
  • 34 Plöckinger U, Krüger D, Bergk A, Weich V, Wiedenmann B, Berg T. Hepatitis-C patients have reduced growth hormone (GH) secretion which improves during long-term therapy with pegylated interferon-alpha. Am J Gastroenterol 2007; 102 (12) 2724-2731
    CrossrefPubMedGoogle Scholar
  • 35 Wu D, Zhang L, Ma S. et al. Low growth hormone levels predict poor outcome of hepatitis B virus-related acute-on-chronic liver failure. Front Med (Lausanne) 2021; 8: 655863
    CrossrefPubMedGoogle Scholar
  • 36 Mohamed AA, Abd-Elsalam S, El-Daly MM. et al. Insulin growth factor-1 as a predictor for the progression of hepatic disease in chronic hepatitis B virus infection. Open Biomark J 2021; 11: 1-7
    CrossrefPubMedGoogle Scholar
  • 37 Helaly GF, Hussein NG, Refai W, Ibrahim M. Relation of serum insulin-like growth factor-1 (IGF-1) levels with hepatitis C virus infection and insulin resistance. Transl Res 2011; 158 (03) 155-162
    CrossrefPubMedGoogle Scholar
  • 38 Ding HG, Shan J, Zhang B. et al. Combined human growth hormone and lactulose for prevention and treatment of multiple organ dysfunction in patients with severe chronic hepatitis B. World J Gastroenterol 2005; 11 (19) 2981-2983
    CrossrefPubMedGoogle Scholar
  • 39 Sato K, Marzioni M, Meng F, Francis H, Glaser S, Alpini G. Ductular reaction in liver diseases: pathological mechanisms and translational significances. Hepatology 2019; 69 (01) 420-430
    CrossrefPubMedGoogle Scholar
  • 40 Wu N, Carpino G, Ceci L. et al. Melatonin receptor 1A, but not 1B, knockout decreases biliary damage and liver fibrosis during cholestatic liver injury. Hepatology 2022; 75 (04) 797-813
    CrossrefPubMedGoogle Scholar
  • 41 Wang K, Wang M, Gannon M, Holterman A. Growth hormone mediates its protective effect in hepatic apoptosis through Hnf6. PLoS One 2016; 11 (12) e0167085
    CrossrefPubMedGoogle Scholar
  • 42 Scopa CD, Koureleas S, Tsamandas AC. et al. Beneficial effects of growth hormone and insulin-like growth factor I on intestinal bacterial translocation, endotoxemia, and apoptosis in experimentally jaundiced rats. J Am Coll Surg 2000; 190 (04) 423-431
    CrossrefPubMedGoogle Scholar
  • 43 Sato K, Glaser S, Kennedy L. et al. Preclinical insights into cholangiopathies: disease modeling and emerging therapeutic targets. Expert Opin Ther Targets 2019; 23 (06) 461-472
    CrossrefPubMedGoogle Scholar
  • 44 Stiedl P, McMahon R, Blaas L. et al. Growth hormone resistance exacerbates cholestasis-induced murine liver fibrosis. Hepatology 2015; 61 (02) 613-626
    CrossrefPubMedGoogle Scholar
  • 45 Cadoret A, Rey C, Wendum D. et al. IGF-1R contributes to stress-induced hepatocellular damage in experimental cholestasis. Am J Pathol 2009; 175 (02) 627-635
    CrossrefPubMedGoogle Scholar
  • 46 Sokolović A, Rodriguez-Ortigosa CM, Bloemendaal LT, Oude Elferink RP, Prieto J, Bosma PJ. Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4(-/-) mice. Biochim Biophys Acta 2013; 1832 (06) 697-704
    CrossrefPubMedGoogle Scholar
  • 47 Alvaro D, Metalli VD, Alpini G. et al. The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis. J Hepatol 2005; 43 (05) 875-883
    CrossrefPubMedGoogle Scholar
  • 48 Gatto M, Drudi-Metalli V, Torrice A. et al. Insulin-like growth factor-1 isoforms in rat hepatocytes and cholangiocytes and their involvement in protection against cholestatic injury. Lab Invest 2008; 88 (09) 986-994
    CrossrefPubMedGoogle Scholar
  • 49 Sato K, Pham L, Glaser S, Francis H, Alpini G. Pathophysiological roles of ductular reaction in liver inflammation and hepatic fibrogenesis. Cell Mol Gastroenterol Hepatol 2022; S2352-345X (22)00239-9. doi: 10.1016/j.jcmgh.2022.11.006
    PubMedGoogle Scholar
  • 50 Boguszewski CL, Boguszewski MCDS. Growth hormone's links to cancer. Endocr Rev 2019; 40 (02) 558-574
    CrossrefPubMedGoogle Scholar
  • 51 Piazza VG, Matzkin ME, Cicconi NS. et al. Exposure to growth hormone is associated with hepatic up-regulation of cPLA2α and COX. Mol Cell Endocrinol 2020; 509: 110802
    CrossrefPubMedGoogle Scholar
  • 52 Chen YJ, You ML, Chong QY. et al. Autocrine human growth hormone promotes invasive and cancer stem cell-like behavior of hepatocellular carcinoma cells by STAT3 dependent inhibition of CLAUDIN-1 expression. Int J Mol Sci 2017; 18 (06) 18
    CrossrefPubMedGoogle Scholar
  • 53 Tolba R, Kraus T, Liedtke C, Schwarz M, Weiskirchen R. Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice. Lab Anim 2015; 49 (01) , Suppl): 59-69
    CrossrefPubMedGoogle Scholar
  • 54 Haque A, Sahu V, Lombardo JL. et al. Disruption of growth hormone receptor signaling abrogates hepatocellular carcinoma development. J Hepatocell Carcinoma 2022; 9: 823-837
    CrossrefPubMedGoogle Scholar
  • 55 Kaseb AO, Haque A, Vishwamitra D. et al. Blockade of growth hormone receptor signaling by using pegvisomant: a functional therapeutic strategy in hepatocellular carcinoma. Front Oncol 2022; 12: 986305
    CrossrefPubMedGoogle Scholar
  • 56 Moore DJ, Adi Y, Connock MJ, Bayliss S. Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation. BMC Endocr Disord 2009; 9: 20
    CrossrefPubMedGoogle Scholar
  • 57 Luo SM, Liang LJ, Lai JM. Effects of recombinant human growth hormone on remnant liver after hepatectomy in hepatocellular carcinoma with cirrhosis. World J Gastroenterol 2004; 10 (09) 1292-1296
    CrossrefPubMedGoogle Scholar
  • 58 Wang Z, Zhou J, Lin J, Wang Y, Lin Y, Li X. RhGH attenuates ischemia injury of intrahepatic bile ducts relating to liver transplantation. J Surg Res 2011; 171 (01) 300-310
    CrossrefPubMedGoogle Scholar
  • 59 Chen WY, White ME, Wagner TE, Kopchick JJ. Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice. Endocrinology 1991; 129 (03) 1402-1408
    CrossrefPubMedGoogle Scholar
  • 60 Pennisi PA, Kopchick JJ, Thorgeirsson S, LeRoith D, Yakar S. Role of growth hormone (GH) in liver regeneration. Endocrinology 2004; 145 (10) 4748-4755
    CrossrefPubMedGoogle Scholar
  • 61 Ishikawa M, Brooks AJ, Fernández-Rojo MA. et al. Growth hormone stops excessive inflammation after partial hepatectomy, allowing liver regeneration and survival through induction of H2-Bl/HLA-G. Hepatology 2021; 73 (02) 759-775
    CrossrefPubMedGoogle Scholar
  • 62 Kineman RD, Del Rio-Moreno M, Sarmento-Cabral A. 40 YEARS of IGF1: Understanding the tissue-specific roles of IGF1/IGF1R in regulating metabolism using the Cre/loxP system. J Mol Endocrinol 2018; 61 (01) T187-T198
    CrossrefPubMedGoogle Scholar
  • 63 Monga SP, Nejak-Bowen K. Ductular reaction and liver regeneration: fulfilling the prophecy of prometheus!. Cell Mol Gastroenterol Hepatol 2022; S2352-345X (22)00240-5. doi: 10.1016/j.jcmgh.2022.11.007
    PubMedGoogle Scholar
  • 64 Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol 2016; 64 (06) 1403-1415
    CrossrefPubMedGoogle Scholar
  • 65 Shekhawat J, Gauba K, Gupta S. et al. Interleukin-6 perpetrator of the COVID-19 cytokine storm. Indian J Clin Biochem 2021; 36 (04) 440-450
    CrossrefPubMedGoogle Scholar
  • 66 Streetz KL, Luedde T, Manns MP, Trautwein C. Interleukin 6 and liver regeneration. Gut 2000; 47 (02) 309-312
    CrossrefPubMedGoogle Scholar
  • 67 Salerno M, Di Maio S, Ferri P, Lettiero T, Di Maria F, Vajro P. Liver abnormalities during growth hormone treatment. J Pediatr Gastroenterol Nutr 2000; 31 (02) 149-151
    CrossrefPubMedGoogle Scholar
  • 68 Swerdlow AJ, Cooke R, Beckers D. et al. Risk of meningioma in European patients treated with growth hormone in childhood: results from the SAGhE cohort. J Clin Endocrinol Metab 2019; 104 (03) 658-664
    CrossrefPubMedGoogle Scholar
  • 69 Boguszewski MCS, Boguszewski CL, Chemaitilly W. et al. Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement. Eur J Endocrinol 2022; 186 (06) 35-P52
    CrossrefPubMedGoogle Scholar
  • 70 Cianfarani S. Risk of cancer in patients treated with recombinant human growth hormone in childhood. Ann Pediatr Endocrinol Metab 2019; 24 (02) 92-98
    CrossrefPubMedGoogle Scholar