Skip to main content

Advertisement

SpringerLink
Log in

FXR overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in alcoholic liver disease

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background and purpose

Alcoholic liver disease (ALD), a metabolic liver disease caused by excessive alcohol consumption, has attracted increasing attention due to its high prevalence and mortality. Up to date, there is no effective and feasible treatment method for ALD. This study was to investigate whether Farnesoid X receptor (FXR, NR1H4) can alleviate ALD and whether this effect is mediated by inhibiting absent in melanoma 2 (AIM2) inflammasome activation.

Methods

The difference in FXR expression between normal subjects and ALD patients was analyzed using the Gene Expression Omnibus (GEO) database. Lieber–DeCarli liquid diet with 5% ethanol (v/v) (EtOH) was adopted to establish the mouse ALD model. Liver histopathological changes and the accumulation of lipid droplets were assessed by H&E and Oil Red O staining. Quantitative real-time PCR, Western blotting analysis and immunofluorescence staining were utilized to evaluate the expression levels of related genes and proteins. DCFH–DA staining was adopted to visualize reactive oxidative species (ROS).

Results

FXR was distinctly downregulated in liver tissues of patients with steatosis compared to normal livers using the GEO database, and in ethanol-induced AML-12 cellular steatosis model. FXR overexpression ameliorated hepatic lipid metabolism disorder and steatosis induced by ethanol by inhibiting the expression of genes involved in lipid synthesis and inducing the expression of genes responsible for lipid metabolism. Besides, FXR overexpression inhibited ethanol-induced AIM2 inflammasome activation and alleviated oxidative stress and ROS production during ethanol-induced hepatic steatosis. However, when FXR was knocked down, the results were completely opposite.

Conclusions

FXR attenuated lipid metabolism disorders and lipid degeneration in alcohol-caused liver injury and alleviated oxidative stress and inflammation by inhibiting AIM2 inflammasome activation.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

All data from this study can be found in the study.

Abbreviations

AIM2:

Absent in melanoma 2

ALD:

Alcoholic liver disease

FXR:

Farnesoid X receptor

IL-1β:

Interleukin-1β

IL-18:

Interleukin-18

ROS:

Reactive oxidative species

TC:

Total cholesterol

TG:

Triglyceride

ASC:

Apoptosis speck-like protein

SREBP1c:

Sterol regulatory element binding protein-1c

FASN:

Fatty acid synthase

SCD-1:

Stearoyl-CoA desaturase-1

CD36:

Platelet glycoprotein 4

CPT1A:

Carnitine palmitoyltransferase 1A

ATGL:

Adipose triglyceride lipase

Caspase-1:

Cysteinyl aspartate-specific proteinase-1

PPARα:

Peroxisome proliferator-activated receptor α

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

FFA:

Free fatty acid

MDA:

Malondialdehyde

CAT:

Catalase

SOD:

Superoxide dismutase

References

  1. Guo M, et al. Dracocephalum tanguticumextracts of maxim ameliorate acute alcoholic liver disease regulating transcription factors in mice. Front Pharmacol. 2022;13:830532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mainz R, et al. NLRP6 inflammasome modulates disease progression in a chronic-plus-binge mouse model of alcoholic liver disease. Cells. 2022;11(2):11020182

    Article  Google Scholar 

  3. Wen B, et al. Targeted treatment of alcoholic liver disease based on inflammatory signalling pathways. Pharmacol Ther. 2021;222:107752

    Article  CAS  PubMed  Google Scholar 

  4. Heo M, et al. Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression. Gut. 2019;68(4):708–720

    Article  CAS  PubMed  Google Scholar 

  5. Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol. 2015;12(4):231–242

    Article  PubMed  Google Scholar 

  6. Sun J, et al. Nrf2 in alcoholic liver disease. Toxicol Appl Pharmacol. 2018;357:62–69

    Article  CAS  PubMed  Google Scholar 

  7. Li Y, et al. NIK links inflammation to hepatic steatosis by suppressing PPARα in alcoholic liver disease. Theranostics. 2020;10(8):3579–3593

    Article  PubMed  PubMed Central  Google Scholar 

  8. Rao P, et al. Prunella vulgaris L. attenuates gut dysbiosis and endotoxin leakage against alcoholic liver disease. J Ethnopharmacol. 2023;319:117237

    Article  PubMed  Google Scholar 

  9. Hu M, et al. viaD-mannose regulates hepatocyte lipid metabolism PI3K/Akt/mTOR signaling pathway and ameliorates hepatic steatosis in alcoholic liver disease. Front Immunol. 2022;13:877650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rangwala F, et al. Increased production of sonic hedgehog by ballooned hepatocytes. J Pathol. 2011;224(3):401–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Forman B, et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell. 1995;81(5):687–693

    Article  CAS  PubMed  Google Scholar 

  12. Fu T, et al. FXR mediates ILC-intrinsic responses to intestinal inflammation. Proc Natl Acad Sci USA. 2022;119(51):e2213041119

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ma S, et al. viaThe protective effects of sulforaphane on high-fat diet-induced metabolic associated fatty liver disease in mice mediating the FXR/LXRα pathway. Food Funct. 2022;13(24):12966–12982

    Article  CAS  PubMed  Google Scholar 

  14. Wang J, et al. Effect of FXR agonist GW4064 in the treatment of hilar cholangiocarcinoma in rats. Sci Rep. 2022;12(1):18873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cui Z, et al. Allium victorialis L. extracts promote activity of FXR to ameliorate alcoholic liver disease: targeting liver lipid deposition and inflammation. Front Pharmacol. 2021;12:738689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xu Z, et al. Dimethyl fumarate attenuates cholestatic liver injury by activating the NRF2 and FXR pathways and suppressing NLRP3/GSDMD signaling in mice. Exp Cell Res. 2023;432(2):113781

    Article  CAS  PubMed  Google Scholar 

  17. Cariou B. The farnesoid X receptor (FXR) as a new target in non-alcoholic steatohepatitis. Diabetes Metab. 2008;34:685–691

    Article  CAS  PubMed  Google Scholar 

  18. Jiang H, et al. Pristimerin suppresses AIM2 inflammasome by modulating AIM2-PYCARD/ASC stability via selective autophagy to alleviate tendinopathy. Autophagy. 2023;2023:1–18

    Google Scholar 

  19. Cao T, et al. Neutrophil extracellular traps promote keratinocyte inflammation via AIM2 inflammasome and AIM2-XIAP in psoriasis. Exp Dermatol. 2023;32(4):368–378

    Article  CAS  PubMed  Google Scholar 

  20. Rossi C, et al. The P2X7R-NLRP3 and AIM2 inflammasome platforms mark the complexity/severity of viral or metabolic liver damage. Int J Mol Sci. 2022;23(13):23137447

    Article  Google Scholar 

  21. Lozano-Ruiz B, González-Navajas J. The emerging relevance of AIM2 in liver disease. Int J Mol Sci. 2020;21(18):21186535

    Article  Google Scholar 

  22. Chen C, et al. The hepatoprotective effects of XCHD and MgIG against methotrexate-induced liver injury and inflammation in rats through suppressing the activation of AIM2 inflammasomes. Pathol Res Pract. 2020;216(4):152875

    Article  CAS  PubMed  Google Scholar 

  23. Xu L, et al. Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease. Am J Physiol Gastrointestinal Liver Physiol. 2021;320(6):G1034–G1044

    Article  CAS  Google Scholar 

  24. Ding L, et al. Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice. Acta pharmaceut Sin B. 2021;11(6):1541–1554

    Article  CAS  Google Scholar 

  25. Valencia-Ortega J, et al. Differential expression of FXR and genes involved in inflammation and lipid metabolism indicate adipose tissue dysfunction in gestational diabetes. Arch Med Res. 2023;54(3):189–196

    Article  CAS  PubMed  Google Scholar 

  26. Chu J, et al. Sinapic acid reduces oxidative stress and pyroptosis via inhibition of BRD4 in alcoholic liver disease. Front Pharmacol. 2021;12:668708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yan R, et al. Ubiquitin-specific protease 22 ameliorates chronic alcohol-associated liver disease by regulating BRD4. Pharmacol Res. 2021;168:105594

    Article  CAS  PubMed  Google Scholar 

  28. Zhou Y, et al. Eight Zhes Decoction ameliorates the lipid dysfunction of nonalcoholic fatty liver disease using integrated lipidomics, network pharmacology and pharmacokinetics. J Pharmaceut Anal. 2023;13(9):1058–1069

    Google Scholar 

  29. Zou J, et al. Ginsenoside Rk2, a dehydroprotopanaxadiol saponin, alleviates alcoholic liver disease via regulating NLRP3 and NLRP6 inflammasome signaling pathways in mice. J Pharmaceut Anal. 2023;13(9):999–1012

    Google Scholar 

  30. Kai J, et al. Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease. Free Radical Biol Med. 2020;153:89–102

    Article  CAS  Google Scholar 

  31. Romero-Gómez M, et al. Nutrition could prevent or promote non-alcoholic fatty liver disease: an opportunity for intervention. BMJ (Clin Res Ed). 2023;383:e075179

    Google Scholar 

  32. Hu Y, et al. Puerarin inhibits inflammation and lipid accumulation in alcoholic liver disease through regulating MMP8. Chin J Nat Med. 2023;21(9):670–681

    CAS  PubMed  Google Scholar 

  33. Liu H, et al. Compound probiotic ameliorates acute alcoholic liver disease in mice by modulating gut microbiota and maintaining intestinal barrier. Probiot Antimicrob Proteins. 2023;15(1):185–201

    Article  CAS  Google Scholar 

  34. Xu M, et al. Targeting inflammation for the treatment of alcoholic liver disease. Pharmacol Ther. 2017;180:77–89

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yang S, et al. Ginsenoside Rh4 improves hepatic lipid metabolism and inflammation in a model of NAFLD by targeting the gut liver axis and modulating the FXR signaling pathway. Foods (Basel, Switzerland). 2023;12(13):1

    Google Scholar 

  36. Jiang B, et al. Prevotella copri ameliorates cholestasis and liver fibrosis in primary sclerosing cholangitis by enhancing the FXR signalling pathway. Biochim Biophys Acta Mol Basis Dis. 2022;1868(3):166320

    Article  CAS  PubMed  Google Scholar 

  37. Li Y, et al. Novel ι-carrageenan tetrasaccharide alleviates liver lipid accumulation via the bile acid-FXR-SHP/PXR pathway to regulate cholesterol conversion and fatty acid metabolism in insulin-resistant mice. J Agric Food Chem. 2021;69(34):9813–9821

    Article  CAS  PubMed  Google Scholar 

  38. Zhang C, et al. Dietary isoquercetin reduces hepatic cholesterol and triglyceride in NAFLD mice by modulating bile acid metabolism via intestinal FXR-FGF15 signaling. J Agric Food Chem. 2023;71(20):7723–7733

    Article  CAS  PubMed  Google Scholar 

  39. Song M, et al. Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR-PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria. FASEB J Off Publ Federation Am Soc Exp Biol. 2020;34(5):7103–7117

    Article  MathSciNet  CAS  Google Scholar 

  40. Sharma M, de Alba E. Structure, activation and regulation of NLRP3 and AIM2 inflammasomes. Int J Mol Sci. 2021;22(2):22020872

    Article  Google Scholar 

  41. Chen S, et al. HBx-mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis. Mol Oncol. 2017;11(9):1225–1240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang Y, et al. Overexpression of NAG-1/GDF15 prevents hepatic steatosis through inhibiting oxidative stress-mediated dsDNA release and AIM2 inflammasome activation. Redox Biol. 2022;52:102322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang B, Niu L, Huang X. Lonicera caerulea juice alleviates alcoholic liver disease by regulating intestinal flora and the FXR-FGF15 signaling pathway. Nutrients. 2023;15(18):15184025

    Article  Google Scholar 

  44. Kong L, et al. Yangonin modulates lipid homeostasis, ameliorates cholestasis and cellular senescence in alcoholic liver disease via activating nuclear receptor FXR. Phytomed Int J Phytother Phytopharmacol. 2021;90:153629

    CAS  Google Scholar 

  45. Yang Y, Cho Y, Hwang S. Crosstalk between oxidative stress and inflammatory liver injury in the pathogenesis of alcoholic liver disease. Int J Mol Sci. 2022;23(2):23020774

    Article  Google Scholar 

  46. Lu Y, et al. Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice. Hepatology (Baltimore, MD). 2008;47(5):1483–1494

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by Natural Science Foundation of Liaoning Province (2023-MS-265).

Author information

Author notes

  1. Lin Li and Lina Kong have contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China

    Lin Li, Lina Kong, Shuai Xu, Changyuan Wang & Qiang Meng

  2. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China

    Jiangning Gu & Haifeng Luo

Authors
  1. Lin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lina Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuai Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Changyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiangning Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Haifeng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qiang Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and methodology and writing—review and editing and funding acquisition: QM; formal analysis and writing—original draft: LL; software and validation and data curation and investigation: LK; visualization: SX; resources: CW; supervision: JG; project administration: HL.

Corresponding author

Correspondence to Qiang Meng.

Ethics declarations

Conflict of interest

Qiang Meng, Lin Li, Lina Kong, Shuai Xu, Changyuan Wang, Jiangning Gu and Haifeng Luo declare that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted and ethical approval was obtained from the Ethics Committee of the Animal Protection and Use Committee of Dalian Medical University (Dalian, China). This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, L., Kong, L., Xu, S. et al. FXR overexpression prevents hepatic steatosis through inhibiting AIM2 inflammasome activation in alcoholic liver disease. Hepatol Int 18, 188–205 (2024). https://doi.org/10.1007/s12072-023-10621-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-023-10621-x

Keywords

Search

Navigation