Stress can attenuate hepatic lipid accumulation via elevation of hepatic β-muricholic acid levels in mice with nonalcoholic steatohepatitis

Abstract

Stress can affect our body and is known to lead to some diseases. However, the influence on the development of nonalcohol fatty liver disease (NAFLD) remains unknown. This study demonstrated that chronic restraint stress attenuated hepatic lipid accumulation via elevation of hepatic β-muricholic acid (βMCA) levels in the development of nonalcoholic steatohepatitis (NASH) in mice. Serum cortisol and corticosterone levels, i.e., human and rodent stress markers, were correlated with serum bile acid levels in patients with NAFLD and methionine- and choline-deficient (MCD) diet-induced mice, respectively, suggesting that stress is related to bile acid (BA) homeostasis in NASH. In the mouse model, hepatic βMCA and cholic acid (CA) levels were increased after the stress challenge. Considering that a short stress enhanced hepatic CYP7A1 protein levels in normal mice and corticosterone increased CYP7A1 protein levels in primary mouse hepatocytes, the enhanced Cyp7a1 expression was postulated to be involved in the chronic stress-increased hepatic βMCA level. Interestingly, chronic stress decreased hepatic lipid levels in MCD-induced NASH mice. Furthermore, βMCA suppressed lipid accumulation in mouse primary hepatocytes exposed to palmitic acid/oleic acid, but CA did not. In addition, Cyp7a1 expression seemed to be related to lipid accumulation in hepatocytes. In conclusion, chronic stress can change hepatic lipid accumulation in NASH mice, disrupting BA homeostasis via induction of hepatic Cyp7a1 expression. This study discovered a new βMCA action in the liver, indicating the possibility that βMCA is available for NAFLD therapy.

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Fig. 1: A correlation between serum cortisol and bile acid levels was observed in both patients with NAFLD and NASH mice.
Fig. 2: Restraint stress enhanced hepatic and serum BA levels in NASH mice.
Fig. 3: Stress-elevated hepatic CYP7A1 protein levels via corticosterone in mice.
Fig. 4: Influence of restraint stress on hepatic lipid levels in NASH mice.
Fig. 5: βMCA can inhibit lipid accumulation in mouse primary hepatocytes.

References

  1. 1.

    Yuan L, Bambha K. Bile acid receptors and nonalcoholic fatty liver disease. World J Hepatol. 2015;7:2811–8.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–65.

    CAS  PubMed  Google Scholar 

  3. 3.

    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.

    PubMed  Google Scholar 

  4. 4.

    Fan JG, Zhu J, Li XJ, Chen L, Lu YS, Li L, et al. Fatty liver and the metabolic syndrome among Shanghai adults. J Gastroenterol Hepatol. 2005;20:1825–32.

    PubMed  Google Scholar 

  5. 5.

    Wong VW, Wong GL, Choi PC, Chan AW, Li MK, Chan HY, et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59:969–74.

    PubMed  Google Scholar 

  6. 6.

    Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–90.

    CAS  PubMed  Google Scholar 

  7. 7.

    Marengo A, Jouness RI, Bugianesi E. Progression and natural history of nonalcoholic fatty liver disease in adults. Clin Liver Dis. 2016;20:313–24.

    PubMed  Google Scholar 

  8. 8.

    Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Investig. 2004;114:147–52.

    CAS  PubMed  Google Scholar 

  9. 9.

    Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52:774–88.

    PubMed  Google Scholar 

  10. 10.

    Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46.

    CAS  PubMed  Google Scholar 

  11. 11.

    Day CP. From fat to inflammation. Gastroenterology. 2006;130:207–10.

    CAS  PubMed  Google Scholar 

  12. 12.

    Tanaka N, Matsubara T, Krausz KW, Patterson AD, Gonzalez FJ. Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis. Hepatology. 2012;56:118–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    van de Wouw M, Boehme M, Lyte JM, Wiley N, Strain C, O’Sullivan O, et al. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations. J Physiol. 2018;596:4923–44.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J Clin Endocrinol Metab. 1998;83:1853–9.

    CAS  PubMed  Google Scholar 

  15. 15.

    Russell AL, Tasker JG, Lucion AB, Fiedler J, Munhoz CD, Wu TJ, et al. Factors promoting vulnerability to dysregulated stress reactivity and stress-related disease. J Neuroendocrinol. 2018;30:e12641.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Nagano J, Nagase S, Sudo N, Kubo C. Psychosocial stress, personality, and the severity of chronic hepatitis C. Psychosomatics. 2004;45:100–6.

    PubMed  Google Scholar 

  17. 17.

    Marsland AL, Cohen S, Rabin BS, Manuck SB. Associations between stress, trait negative affect, acute immune reactivity, and antibody response to hepatitis B injection in healthy young adults. Health Psychol. 2001;20:4–11.

    CAS  PubMed  Google Scholar 

  18. 18.

    Hagio M, Matsumoto M, Fukushima M, Hara H, Ishizuka S. Improved analysis of bile acids in tissues and intestinal contents of rats using LC/ESI-MS. J Lipid Res. 2009;50:173–80.

    CAS  PubMed  Google Scholar 

  19. 19.

    Matsubara T, Tanaka N, Patterson AD, Cho JY, Krausz KW, Gonzalez FJ. Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice. Hepatology. 2011;53:1282–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Aranha MM, Cortez-Pinto H, Costa A, da Silva IB, Camilo ME, de Moura MC, et al. Bile acid levels are increased in the liver of patients with steatohepatitis. Eur J Gastroenterol Hepatol. 2008;20:519–25.

    CAS  PubMed  Google Scholar 

  21. 21.

    Ferslew BC, Xie G, Johnston CK, Su M, Stewart PW, Jia W, et al. Altered bile acid metabolome in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2015;60:3318–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Suga T, Yamaguchi H, Ogura J, Shoji S, Maekawa M, Mano N. Altered bile acid composition and disposition in a mouse model of non-alcoholic steatohepatitis. Toxicol Appl Pharmacol. 2019;379:114664.

    CAS  PubMed  Google Scholar 

  23. 23.

    Dawson PA, Hubbert M, Haywood J, Craddock AL, Zerangue N, Christian WV, et al. The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. J Biol Chem. 2005;280:6960–8.

    CAS  PubMed  Google Scholar 

  24. 24.

    Rius M, Hummel-Eisenbeiss J, Hofmann AF, Keppler D. Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione. Am J Physiol Gastrointest Liver Physiol. 2006;290:G640–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Silvennoinen R, Quesada H, Kareinen I, Julve J, Kaipiainen L, Gylling H, et al. Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice. Physiol Rep. 2015;3:e12402.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Lavoie J-M. Dynamics of hepatic and intestinal cholesterol and bile acid pathways: The impact of the animal model of estrogen deficiency and exercise training. World J Hepatol. 2016;8:961–75.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Liu X, Xue R, Yang C, Gu J, Chen S, Zhang S. Cholestasis-induced bile acid elevates estrogen level via farnesoid X receptor-mediated suppression of the estrogen sulfotransferase SULT1E1. J Biol Chem. 2018;293:12759–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Adcock IM, Mumby S. Glucocorticoids. Handb Exp Pharmacol. 2017;237:171–96.

    CAS  PubMed  Google Scholar 

  29. 29.

    Mitropoulos KA, Balasubramaniam S. The role of glucocorticoids in the regulation of the diurnal rhythm of hepatic beta-hydroxy-beta-methylglutaryl-coenzyme A reductase and cholesterol 7 alpha-hydroxylase. Biochem J. 1976;160:49–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Out C, Dikkers A, Laskewitz A, Boverhof R, van der Ley C, Kema IP, et al. Prednisolone increases enterohepatic cycling of bile acids by induction of Asbt and promotes reverse cholesterol transport. J Hepatol. 2014;61:351–7.

    CAS  PubMed  Google Scholar 

  31. 31.

    Xiao Y, Yan W, Zhou K, Cao Y, Cai W. Glucocorticoid treatment alters systemic bile acid homeostasis by regulating the biosynthesis and transport of bile salts. Dig Liver Dis. 2016;48:771–9.

    CAS  PubMed  Google Scholar 

  32. 32.

    Li T, Chanda D, Zhang Y, Choi HS, Chiang JY. Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes. J Lipid Res. 2010;51:832–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Li T, Kong X, Owsley E, Ellis E, Strom S, Chiang JY. Insulin regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c. J Biol Chem. 2006;281:28745–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, et al. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism. 2011;60:404–13.

    CAS  PubMed  Google Scholar 

  35. 35.

    Lake AD, Novak P, Shipkova P, Aranibar N, Robertson D, Reily MD, et al. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease. Toxicol Appl Pharmacol. 2013;268:132–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Puri P, Daita K, Joyce A, Mirshahi F, Santhekadur PK, Cazanave S, et al. The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids. Hepatology. 2018;67:534–48.

    CAS  PubMed  Google Scholar 

  37. 37.

    Attili AF, Angelico M, Cantafora A, Alvaro D, Capocaccia L. Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses. 1986;19:57–69.

    CAS  PubMed  Google Scholar 

  38. 38.

    Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000;6:517–26.

    CAS  PubMed  Google Scholar 

  39. 39.

    Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17:225–35.

    CAS  PubMed  Google Scholar 

  40. 40.

    Konstandi M, Shah YM, Matsubara T, Gonzalez FJ. Role of PPARalpha and HNF4alpha in stress-mediated alterations in lipid homeostasis. PLoS ONE. 2013;8:e70675.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Tanaka N, Takahashi S, Matsubara T, Jiang C, Sakamoto W, Chanturiya T, et al. Adipocyte-specific disruption of fat-specific protein 27 causes hepatosteatosis and insulin resistance in high-fat diet-fed mice. J Biol Chem. 2015;290:3092–105.

    CAS  PubMed  Google Scholar 

  42. 42.

    Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Delavier-Klutchko C, et al. Molecular characterization of the human beta 3-adrenergic receptor. Science. 1989;245:1118–21.

    CAS  PubMed  Google Scholar 

  43. 43.

    Machado MV, Michelotti GA, Xie G, Almeida Pereira T, Boursier J, Bohnic B, et al. Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS ONE. 2015;10:e0127991.

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Li T, Owsley E, Matozel M, Hsu P, Novak CM, Chiang JY. Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice. Hepatology. 2010;52:678–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Qi Y, Jiang C, Cheng J, Krausz KW, Li T, Ferrell JM, et al. Bile acid signaling in lipid metabolism: metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice. Biochim Biophys Acta. 2015;1851:19–29.

    CAS  PubMed  Google Scholar 

  46. 46.

    Jelinek DF, Andersson S, Slaughter CA, Russell DW. Cloning and regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. J Biol Chem. 1990;265:8190–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Myant NB, Mitropoulos KA. Cholesterol 7 alpha-hydroxylase. J Lipid Res. 1977;18:135–53.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Tadashi Mizutani, Kenji Kitamura, Chiho Kanodo, Kanako Fukuda (Osaka City University Graduate School of Medicine) and the Research Support Platform of Osaka City University Graduate School of Medicine for technical assistance. This work was supported by Osaka City University Strategic Research Grants 2012 and 2013 for young researchers (to TM), Takeda Science Foundation (to TM), JSPS KAKENHI Grant Numbers JP26870501 and 17K18012 (to TM), and Gilead Sciences (to HF and NK).

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Correspondence to Tsutomu Matsubara.

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Takada, S., Matsubara, T., Fujii, H. et al. Stress can attenuate hepatic lipid accumulation via elevation of hepatic β-muricholic acid levels in mice with nonalcoholic steatohepatitis. Lab Invest 101, 193–203 (2021). https://doi.org/10.1038/s41374-020-00509-x

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