FGF21 alleviates acute liver injury by inducing the SIRT1‐autophagy signalling pathway

Abstract

Liver injury can lead to different hepatic diseases, which are the mainly causes of high global mortality and morbidity. Autophagy and Sirtuin type 1 (SIRT1) have been shown protective effects in response to liver injury. Previous studies have showed that Fibroblast growth factor 21 (FGF21) could alleviate acute liver injury (ALI), but the mechanism remains unclear. Here, we verified the relationship among FGF21, autophagy and SIRT1 in carbon tetrachloride (CCl4)‐induced ALI. We established CCl4‐induced ALI models in C57BL/6 mice and the L02 cell line. The results showed that FGF21 was robustly induced in response to stress during the development of ALI. After exogenous FGF21 treatment in ALI models, liver damage in ALI mice was significantly reduced, as well as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Consistently, FGF21 also greatly reduced the levels of ALT, AST, pro‐inflammatory cytokines interleukin 6 (IL6) and tumour necrosis factor‐alpha (TNFα) in ALI cell lines. Mechanistically, exogenous FGF21 treatment efficiently upregulated the expression of autophagy marker microtubule‐associated protein light chain‐3 beta (LC3 II) and autophagy key molecule coiled‐coil myosin‐like BCL2‐interacting protein (Beclin1), which was accompanied by alleviating hepatotoxicity in CCl4‐treated wild‐type mice. Then, we examined how FGF21 induced autophagy expression and found that SIRT1 was also upregulated by FGF21 treatment. To further verify our results, we constructed an anti‐SIRT1 lentit‐RNAi to inhibit SIRT1 expression in mice and L02 cells, which reversed the protective effect of FGF21 on ALI. In summary, these results indicate that FGF21 alleviates ALI by enhancing SIRT1‐mediated autophagy.

Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation

“…However, the incidence of acute liver injury (ALI) has gradually increased due to viral infections, improper medications, excessive intake and exposure of food additives, ethanol, ingestion of toxic foods, and radiation injury ( Bechmann et al, 2012 ; Chao et al, 2018 ; LoBianco et al, 2020 ; Xu et al, 2020 ). ALI refers to acute injury or necrosis of liver cells, abnormal liver function, and even liver failure in some patients ( Yang et al, 2022 ). Although liver cells have a strong ability to regenerate, ALI still threaten life if they are not treated in time.…”

RNF115/BCA2 deficiency alleviated acute liver injury in mice by promoting autophagy and inhibiting inflammatory response

“…Autophagy inhibits TNF toxicity by blocking caspase 8 activation and mitochondrial death pathways in vivo, suggesting that autophagy is a potential therapeutic target in the treatment of TNF-α-induced liver injury [31]. Fibroblast growth factor 21 was recently found to attenuate CCl4-induced ALI through SIRT1speci c mediated autophagy-induced expression [32]. A previous study in our laboratory showed that enhanced autophagy accelerated the clearance of damaged mitochondria in drug-induced ALI in mice, thus providing a protective effect [14].…”

The role of sirtuin1 in liver injury: molecular mechanisms and novel therapeutic target

“…SIRT1 induction by FGF21 enhances autophagy and reduces inflammation, which helps protect against CCl4-induced liver injury ( Yang et al, 2022b ). This suggests that the presence and activation of SIRT1 are crucial for mitigating liver injury and, by extension, preventing fibrosis.…”