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Restraint stress promotes nonalcoholic steatohepatitis by regulating the farnesoid X receptor/NLRP3 signaling pathway.

ABSTRACT: Psychological stress promotes nonalcoholic steatohepatitis (NASH) development. However, the pathogenesis of psychological stress-induced NASH remains unclear. This study aims to explore the underlying mechanism of restraint stress-induced NASH, which mimics psychological stress, and to discover potential NASH candidates. Methionine choline deficient diet- and high fat diet-induced hepatosteatotic mice are subjected to restraint stress to induce NASH. The mice are administrated with Xiaoyaosan granules, NOD-like receptor family pyrin domain containing 3 (NLRP3) inhibitors, farnesoid X receptor (FXR) agonists, or macrophage scavengers. Pathological changes and NLRP3 signaling in the liver are determined. These results demonstrate that restraint stress promotes hepatic inflammation and fibrosis in hepatosteatotic mice. Restraint stress increases the expressions of NLRP3, Caspase-1, Gasdermin D, interleukin-1β, cholesterol 7α-hydroxylase, and sterol 12α-hydroxylase and decreases the expression of FXR in NASH mice. Xiaoyaosan granules reverse hepatic inflammation and fibrosis and target FXR and NLRP3 signals. In addition, inhibition of NLRP3 reduces the NLRP3 inflammasome and liver damage in mice with restraint stress-induced NASH. Elimination of macrophages and activation of FXR also attenuate inflammation and fibrosis by inhibiting NLRP3 signaling. However, NLRP3 inhibitors or macrophage scavengers fail to affect the expression of FXR. In conclusion, restraint stress promotes NASH-related inflammation and fibrosis by regulating the FXR/NLRP3 signaling pathway. Xiaoyaosan granules, NLRP3 inhibitors, FXR agonists, and macrophage scavengers are potential candidates for the treatment of psychological stress-related NASH.

SUBMITTER: Yang F

PROVIDER: S-EPMC10753372 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Restraint stress promotes nonalcoholic steatohepatitis by regulating the farnesoid X receptor/NLRP3 signaling pathway.

Yang Fan F Lv Xi-Ting XT Lin Xiao-Li XL Wang Ruo-Hong RH Wang Shu-Mei SM Wang Guo-En GE

Acta biochimica et biophysica Sinica 20231201 12

Psychological stress promotes nonalcoholic steatohepatitis (NASH) development. However, the pathogenesis of psychological stress-induced NASH remains unclear. This study aims to explore the underlying mechanism of restraint stress-induced NASH, which mimics psychological stress, and to discover potential NASH candidates. Methionine choline deficient diet- and high fat diet-induced hepatosteatotic mice are subjected to restraint stress to induce NASH. The mice are administrated with Xiaoyaosan gr ...[more]

PMID: 37997375

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Project description:The activated c-Jun N-terminal kinase (JNK) specifically combined with SH3 domain-binding protein 5 (Sab) may mediate damage to the mitochondrial respiratory chain. Whether mitochondrial dysfunction induced by the JNK/Sab signaling pathway plays a pivotal role in the lipotoxic injury of nonalcoholic steatohepatitis (NASH) remains a lack of evidence. Scoparone, a natural compound from Traditional Chinese Medicine herbs, has the potential for liver protection and lipid metabolism regulation. However, the effect of scoparone on NASH induced by a high-fat diet (HFD) as well as its underlying mechanism remains to be elucidated. The HepG2 and Huh7 cells with/without Sab-knockdown induced by palmitic acid (PA) were used to determine the role of JNK/Sab signaling in mitochondrial dysfunction and cellular lipotoxic injury. To observe the effect of scoparone on the lipotoxic injured hepatocytes, different dose of scoparone together with PA was mixed into the culture medium of HepG2 and AML12 cells to incubate for 24 h. In addition, male C57BL/6J mice were fed with an HFD for 22 weeks to induce the NASH model and were treated with scoparone for another 8 weeks to investigate its effect on NASH. Molecules related to JNK/Sab signaling, mitochondrial function, and lipotoxic injury were detected in in vitro and/or in vivo experiments. The results showed that PA-induced activation of JNK/Sab signaling was blocked by Sab knockdown in hepatocytes, which improved mitochondrial damage, oxidative stress, hepatosteatosis, cell viability, and apoptosis. Scoparone demonstrated a similar effect on the PA-induced hepatocytes as Sab knockdown. For the NASH mice, treatment with scoparone also downregulated the activation of JNK/Sab signaling, improved histopathological changes of liver tissues including mitochondrial number and morphology, lipid peroxide content, hepatosteatosis and inflammation obviously, as well as decreased the serum level of lipid and transaminases. Taken together, this study confirms that activation of the JNK/Sab signaling pathway-induced mitochondrial dysfunction plays a crucial role in the development of NASH. Scoparone can improve the lipotoxic liver injury partially by suppressing this signaling pathway, making it a potential therapeutic compound for NASH.

Project description:Background/aimsThe molecular mechanisms driving nonalcoholic steatohepatitis (NASH) progression are poorly understood. This research examines the involvement of chaperone-mediated autophagy (CMA) in NASH progression.MethodsHepatic CMA activity was analysed in NASH mice and patients. Lysosome-associated membrane protein 2A (LAMP2A) was knocked down or overexpressed to assess the effects of hepatocyte-specific CMA on NASH progression. Mice received a high-fat diet or a methionine and choline-deficient diet to induce NASH. Palmitic acid was employed to mimic lipotoxicity-induced hepatocyte damage in vitro. The promoter activity of FOXM1 was evaluated via ChIP and dual-luciferase reporter assays.ResultsHepatic CMA activity was substantially low in NASH mice and patients. LAMP2A knockdown resulted in hepatocyte-specific CMA deficiency, which promoted fibrosis and hepatic inflammation in NASH mice. Both in vitro and in vivo, CMA deficiency also exacerbated hepatocyte damage and endoplasmic reticulum (ER) stress. Mechanistically, CMA deficiency in hepatocytes increased cholesterol accumulation by blocking the degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCR), a key cholesterol synthesis-related enzyme, and the accumulated cholesterol subsequently induced ER stress and hepatocyte damage. The restoration of hepatocyte-specific CMA activity effectively ameliorated diet-induced NASH and ER stress in vivo and in vitro. FOXM1 directly bound to LAMP2A promoter and negatively regulated its transcription. The upregulation of FOXM1 expression impaired CMA and enhanced ER stress, which in turn increased FOXM1 expression, resulting in a vicious cycle and promoting NASH development.ConclusionsThis study highlights the significance of the FOXM1/CMA/ER stress axis in NASH progression and proposes novel therapeutic targets for NASH.Key pointsChaperone-mediated autophagy (CMA) deficiency in hepatocytes promotes hepatic inflammation and fibrosis in mice with nonalcoholic steatohepatitis (NASH) by inducing cholesterol accumulation and endoplasmic reticulum (ER) stress. Upregulated FOXM1 impairs CMA by suppressing the transcription of lysosome-associated membrane protein 2A (LAMP2A), a rate-limiting component of CMA. ER stress increases FOXM1 expression and cholesterol accumulation. FOXM1/CMA/ER stress axis forms a vicious circle and promotes the development of NASH.

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Restraint stress promotes nonalcoholic steatohepatitis by regulating the farnesoid X receptor/NLRP3 signaling pathway.

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Restraint stress promotes nonalcoholic steatohepatitis by regulating the farnesoid X receptor/NLRP3 signaling pathway.

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