Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats
HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvasta...
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2025-07-01
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| author | Engy A. Elsiad Hayat A. Abd El Aal Hesham A. Salem Mohammed F. El-Yamany Mostafa A. Rabie |
| author_facet | Engy A. Elsiad Hayat A. Abd El Aal Hesham A. Salem Mohammed F. El-Yamany Mostafa A. Rabie |
| author_sort | Engy A. Elsiad |
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| description | HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. |
| format | Article |
| id | doaj-art-f287ee6e1b204343b51b3779f297c9c4 |
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| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-f287ee6e1b204343b51b3779f297c9c42025-07-25T13:37:39ZengMDPI AGToxics2305-63042025-07-0113759410.3390/toxics13070594Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar RatsEngy A. Elsiad0Hayat A. Abd El Aal1Hesham A. Salem2Mohammed F. El-Yamany3Mostafa A. Rabie4Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptDepartment of Clinical, Bio-in Molecules, Egyptian Drug Authority (EDA), Cairo 11553, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptHMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis.https://www.mdpi.com/2305-6304/13/7/594atorvastatinliraglutidehepatotoxicityGLP-1R/Aktautophagy |
| spellingShingle | Engy A. Elsiad Hayat A. Abd El Aal Hesham A. Salem Mohammed F. El-Yamany Mostafa A. Rabie Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats Toxics atorvastatin liraglutide hepatotoxicity GLP-1R/Akt autophagy |
| title | Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats |
| title_full | Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats |
| title_fullStr | Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats |
| title_full_unstemmed | Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats |
| title_short | Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats |
| title_sort | liraglutide attenuates atorvastatin induced hepatotoxicity by restoring glp 1r expression and activating nrf2 and autophagy pathways in wistar rats |
| topic | atorvastatin liraglutide hepatotoxicity GLP-1R/Akt autophagy |
| url | https://www.mdpi.com/2305-6304/13/7/594 |
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