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.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Yuan L, Bambha K. Bile acid receptors and nonalcoholic fatty liver disease. World J Hepatol. 2015;7:2811–8.
Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–65.
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.
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.
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.
Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–90.
Marengo A, Jouness RI, Bugianesi E. Progression and natural history of nonalcoholic fatty liver disease in adults. Clin Liver Dis. 2016;20:313–24.
Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Investig. 2004;114:147–52.
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52:774–88.
Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46.
Day CP. From fat to inflammation. Gastroenterology. 2006;130:207–10.
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.
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.
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.
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.
Nagano J, Nagase S, Sudo N, Kubo C. Psychosocial stress, personality, and the severity of chronic hepatitis C. Psychosomatics. 2004;45:100–6.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Adcock IM, Mumby S. Glucocorticoids. Handb Exp Pharmacol. 2017;237:171–96.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Myant NB, Mitropoulos KA. Cholesterol 7 alpha-hydroxylase. J Lipid Res. 1977;18:135–53.
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).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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