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


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.


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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).

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