Atorvastatin Attenuates Diet-Induced Non-Alcoholic Steatohepatitis in APOE*3-Leiden Mice by Reducing Hepatic Inflammation
Patients with metabolic syndrome are often prescribed statins to prevent the development of cardiovascular disease. Conversely, data on their effects on non-alcoholic steatohepatitis (NASH) are lacking. We evaluated these effects by feeding APOE*3-Leiden mice a Western-type diet (WTD) with or withou...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/9/7818 |
| _version_ | 1797602505600794624 |
|---|---|
| author | José A. Inia Geurt Stokman Elsbet J. Pieterman Martine C. Morrison Aswin L. Menke Lars Verschuren Martien P. M. Caspers Martin Giera J. Wouter Jukema Anita M. van den Hoek Hans M. G. Princen |
| author_facet | José A. Inia Geurt Stokman Elsbet J. Pieterman Martine C. Morrison Aswin L. Menke Lars Verschuren Martien P. M. Caspers Martin Giera J. Wouter Jukema Anita M. van den Hoek Hans M. G. Princen |
| author_sort | José A. Inia |
| collection | DOAJ |
| description | Patients with metabolic syndrome are often prescribed statins to prevent the development of cardiovascular disease. Conversely, data on their effects on non-alcoholic steatohepatitis (NASH) are lacking. We evaluated these effects by feeding APOE*3-Leiden mice a Western-type diet (WTD) with or without atorvastatin to induce NASH and hepatic fibrosis. Besides the well-known plasma cholesterol lowering (−30%) and anti-atherogenic effects (severe lesion size −48%), atorvastatin significantly reduced hepatic steatosis (−22%), the number of aggregated inflammatory cells in the liver (−80%) and hepatic fibrosis (−92%) compared to WTD-fed mice. Furthermore, atorvastatin-treated mice showed less immunohistochemically stained areas of inflammation markers. Atorvastatin prevented accumulation of free cholesterol in the form of cholesterol crystals (−78%). Cholesterol crystals are potent inducers of the NLRP3 inflammasome pathway and atorvastatin prevented its activation, which resulted in reduced expression of the pro-inflammatory cytokines interleukin (IL)-1β (−61%) and IL-18 (−26%). Transcriptome analysis confirmed strong reducing effects of atorvastatin on inflammatory mediators, including NLRP3, NFκB and TLR4. The present study demonstrates that atorvastatin reduces hepatic steatosis, inflammation and fibrosis and prevents cholesterol crystal formation, thereby precluding NLRP3 inflammasome activation. This may render atorvastatin treatment as an attractive approach to reduce NAFLD and prevent progression into NASH in dyslipidemic patients. |
| first_indexed | 2024-03-11T04:16:57Z |
| format | Article |
| id | doaj.art-351090f3a1f1422592706f73e3662541 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:16:57Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-351090f3a1f1422592706f73e36625412023-11-17T23:01:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01249781810.3390/ijms24097818Atorvastatin Attenuates Diet-Induced Non-Alcoholic Steatohepatitis in APOE*3-Leiden Mice by Reducing Hepatic InflammationJosé A. Inia0Geurt Stokman1Elsbet J. Pieterman2Martine C. Morrison3Aswin L. Menke4Lars Verschuren5Martien P. M. Caspers6Martin Giera7J. Wouter Jukema8Anita M. van den Hoek9Hans M. G. Princen10Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsDepartment of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsDepartment of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsCenter for Proteomics and Metabolomics, Leiden University Medical Center (LUMC), 2333 ZC Leiden, The NetherlandsDepartment of Cardiology, Leiden University Medical Center (LUMC), 2333 ZA Leiden, The NetherlandsDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsDepartment of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 BE Leiden, The NetherlandsPatients with metabolic syndrome are often prescribed statins to prevent the development of cardiovascular disease. Conversely, data on their effects on non-alcoholic steatohepatitis (NASH) are lacking. We evaluated these effects by feeding APOE*3-Leiden mice a Western-type diet (WTD) with or without atorvastatin to induce NASH and hepatic fibrosis. Besides the well-known plasma cholesterol lowering (−30%) and anti-atherogenic effects (severe lesion size −48%), atorvastatin significantly reduced hepatic steatosis (−22%), the number of aggregated inflammatory cells in the liver (−80%) and hepatic fibrosis (−92%) compared to WTD-fed mice. Furthermore, atorvastatin-treated mice showed less immunohistochemically stained areas of inflammation markers. Atorvastatin prevented accumulation of free cholesterol in the form of cholesterol crystals (−78%). Cholesterol crystals are potent inducers of the NLRP3 inflammasome pathway and atorvastatin prevented its activation, which resulted in reduced expression of the pro-inflammatory cytokines interleukin (IL)-1β (−61%) and IL-18 (−26%). Transcriptome analysis confirmed strong reducing effects of atorvastatin on inflammatory mediators, including NLRP3, NFκB and TLR4. The present study demonstrates that atorvastatin reduces hepatic steatosis, inflammation and fibrosis and prevents cholesterol crystal formation, thereby precluding NLRP3 inflammasome activation. This may render atorvastatin treatment as an attractive approach to reduce NAFLD and prevent progression into NASH in dyslipidemic patients.https://www.mdpi.com/1422-0067/24/9/7818atorvastatinNAFLDNASHinflammationfibrosisinflammasomes |
| spellingShingle | José A. Inia Geurt Stokman Elsbet J. Pieterman Martine C. Morrison Aswin L. Menke Lars Verschuren Martien P. M. Caspers Martin Giera J. Wouter Jukema Anita M. van den Hoek Hans M. G. Princen Atorvastatin Attenuates Diet-Induced Non-Alcoholic Steatohepatitis in APOE*3-Leiden Mice by Reducing Hepatic Inflammation International Journal of Molecular Sciences atorvastatin NAFLD NASH inflammation fibrosis inflammasomes |
| title | Atorvastatin Attenuates Diet-Induced Non-Alcoholic Steatohepatitis in APOE*3-Leiden Mice by Reducing Hepatic Inflammation |
| title_full | Atorvastatin Attenuates Diet-Induced Non-Alcoholic Steatohepatitis in APOE*3-Leiden Mice by Reducing Hepatic Inflammation |
| title_fullStr | Atorvastatin Attenuates Diet-Induced Non-Alcoholic Steatohepatitis in APOE*3-Leiden Mice by Reducing Hepatic Inflammation |
| title_full_unstemmed | Atorvastatin Attenuates Diet-Induced Non-Alcoholic Steatohepatitis in APOE*3-Leiden Mice by Reducing Hepatic Inflammation |
| title_short | Atorvastatin Attenuates Diet-Induced Non-Alcoholic Steatohepatitis in APOE*3-Leiden Mice by Reducing Hepatic Inflammation |
| title_sort | atorvastatin attenuates diet induced non alcoholic steatohepatitis in apoe 3 leiden mice by reducing hepatic inflammation |
| topic | atorvastatin NAFLD NASH inflammation fibrosis inflammasomes |
| url | https://www.mdpi.com/1422-0067/24/9/7818 |
| work_keys_str_mv | AT joseainia atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT geurtstokman atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT elsbetjpieterman atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT martinecmorrison atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT aswinlmenke atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT larsverschuren atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT martienpmcaspers atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT martingiera atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT jwouterjukema atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT anitamvandenhoek atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation AT hansmgprincen atorvastatinattenuatesdietinducednonalcoholicsteatohepatitisinapoe3leidenmicebyreducinghepaticinflammation |