Abstract
Chronic inflammation in response to persistent exogenous stimuli or damage results in liver fibrosis, which subsequently progresses into malignant liver diseases with high morbidity and mortality. Ferulic acid (FA) is a phenolic acid widely isolated from abundant plants and exhibits multiple biological activities including anti-oxidant, anti-inflammation and enhancement of immune responses. Adenosine monophosphate-activated protein kinase (AMPK) functions as a critical energy sensor and is regulated through the phosphorylation of liver kinases like LKB1 or dephosphorylation by protein tyrosine phosphatases (PTPs). However, the role of FA in carbon tetrachloride (CCl4)-induced chronic inflammation and liver fibrosis and AMPK activation has not been elucidated. Here we reported that FA ameliorated CCl4-induced inflammation and fibrotic liver damage in mice as indicated by reduced levels of serum liver function enzyme activities and decreased expression of genes and proteins associated with fibrogenesis. Additionally, FA inhibited hepatic oxidative stress, macrophage activation and HSC activation via AMPK phosphorylation in different liver cells. Mechanically, without the participation of LKB1, FA-induced anti-inflammatory and anti-fibrotic effects were abrogated by a specific AMPK inhibitor, compound C. Combining with the results of molecular docking, surface plasmon resonance and co-immunoprecipitation assays, we further demonstrated that FA directly bound to and inhibited PTP1B, an enzyme responsible for dephosphorylating key protein kinases, and eventually leading to the phosphorylation of AMPK. In summary, our results indicated that FA alleviated oxidative stress, hepatic inflammation and fibrotic response in livers through PTP1B-AMPK signaling pathways. Taken together, we provide novel insights into the potential of FA as a natural product-derived therapeutic agent for the treatment of fibrotic liver injury.
Highlights
Liver fibrosis is a dynamic process leading to inflammatory cascades, excessive deposition of extracellular matrix (ECM) and the formation of fibrous scars
Serum biochemistry assays showed that carbon tetrachloride (CCl4) significantly increased the serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), which were all markedly reversed by ferulic acid (FA) administration (Figure 1B)
We recently reported that the aberrant expression of long noncoding RNA H19 was responsible for hepatic stellate cell (HSC) activation and liver fibrosis progression in multiple mouse models (Wang et al, 2021)
Summary
Liver fibrosis is a dynamic process leading to inflammatory cascades, excessive deposition of extracellular matrix (ECM) and the formation of fibrous scars. With persistent inflammatory stimuli or exogenous damage, liver fibrosis is becoming a leading cause of cirrhosis and hepatocellular carcinoma with high morbidity and mortality (Kisseleva, 2017). Underlying etiologies in fibrotic liver injury comprise but not limited to viral infection, alcoholic or nonalcoholic steatohepatitis, oxidative stress and exogenous noxious stimuli (Parola and Pinzani, 2019). Besides the reduced adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio caused by any cellular stress (Li et al, 2015), the phosphorylation of extracellular-signal-regulated protein kinase 1/2 (ERK1/2) and liver kinase B1 (LKB1) are the major upstream signal cascades of AMPK activation (Li et al, 2017). Once the activation of AMPK was decreased, proapoptotic caspase-6 cleaved Bid to induce cytochrome c release that led to hepatocyte damage and fibrotic liver injury (Zhao et al, 2020). Considering the vital role that AMPK plays in the progression of fibrotic liver injury, the identification of novel drugs targeting AMPK is urgently needed
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