Long-Term Consumption of Food-Derived Chlorogenic Acid Protects Mice against Acetaminophen-Induced Hepatotoxicity via Promoting PINK1-Dependent Mitophagy and Inhibiting Apoptosis

Abstract

Hepatotoxicity brought on by acetaminophen (APAP) is significantly impacted by mitochondrial dysfunction. Mitophagy, particularly PINK1-mediated mitophagy, maintains the stability of cell function by eliminating damaged mitochondria. One of the most prevalent dietary polyphenols, chlorogenic acid (CGA), has been shown to have hepatoprotective properties. It is yet unknown, nevertheless, whether its defense against hepatocyte apoptosis involves triggering PINK1-mediated mitophagy. In vitro and in vivo models of APAP-induced hepatotoxicity were established to observe CGA’s effect and mechanism in preventing hepatotoxicity in the present study. Serum aminotransferase levels, mouse liver histology, and the survival rate of HepG2 cells and mice were also assessed. The outcomes showed that CGA could reduce the activities of serum enzymes such as alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH), and alleviate liver injury in mice. It could also significantly increase the cell viability of HepG2 cells and the 24-h survival rate of mice. TUNEL labeling and Western blotting were used to identify the hepatocyte apoptosis level. According to data, CGA could significantly reduce liver cell apoptosis in vivo. Additionally, Tom20 and LC3II colocalization in mitochondria may be facilitated by CGA. CGA considerably increased the levels of genes and proteins associated with mitophagy (PINK1, Parkin, LC3II/LC3I), while considerably decreasing the levels of p62 and Tom20, suggesting that it might activate PINK1/Parkin-mediated mitophagy in APAP-induced liver damage. Additionally, the protection of CGA was reduced when PINK1 was knocked down by siPINK1 in HepG2 cells, and it did not upregulate mitophagy-related proteins (PINK1, Parkin, LC3II/LC3I). In conclusion, our findings revealed that long-term consumption of food-derived CGA could prevent APAP hepatotoxicity via increasing PINK1-dependent mitophagy and inhibiting hepatocyte apoptosis.

BTF3L4 Overexpression Mediates APAP-induced Liver Injury in Mouse and Cellular Models

“… 6 , 39 Increased apoptosis may thus reduce hepatic injury by triggering a switch to necroptosis through the activation of the TNF signaling pathway during AILI. Consistent with previous studies, 40 , 41 we found that apoptosis was increased in AILI animal and hepatic models. In vitro , we demonstrated that the apoptosis and TNF-α levels were regulated by BTF3L4 in normal liver cells without any treatment.…”

Acetaminophen-induced liver injury: Molecular mechanism and treatments from natural products

“…Studies have shown that the hepatotoxicity of APAP can lead to mitochondrial dysfunction and affect PINK1-mediated mitosis. Chlorogenic acid stabilizes cell function by eliminating mitochondrial damage, increases PINK1-dependent mitosis, inhibits apoptosis of liver cells, and prevents APAP hepatotoxicity ( Hu et al, 2022 ). Currently, chlorogenic acid is considered a promising hepatic detoxifier for APAP.…”

Chlorogenic Acid: A Systematic Review on the Biological Functions, Mechanistic Actions, and Therapeutic Potentials

“…CGA mitigates acetaminophen-induced hepatic injuries by inhibiting apoptosis and oxidation, ameliorating liver inflammation, activating Nrf2, promoting mitophagy, and suppressing activities of metabolic enzymes such as cytochrome P450 (CYP) [20,24,[150][151][152][153][154]. CGA can ameliorate hepatotoxicity triggered by many other drugs including tamoxifen, methotrexate, triptolide, and monocrotaline [155][156][157][158].…”

“…Anti-inflammatory and oxidative effects (Sections 2.1 and 2.3) Macrophage [32]; 3T3-L1 cells [27]; carbon tetrachloride or acetaminophen-induced liver injury in mice [20,23,24] Weaned Pigs, LPS-induced mice, I/R rat liver injury, endotoxic shock-induced acute liver injury [28,30,31,33] Suppressing TLR4, TNF-α, NF-κB, and MAPK pathways [28][29][30][31]; activation of CD36/AMPK/PGC-1α [32] and Nrf2 signaling [20,34- Metals, chemicals, and toxins: sodium arsenite [137], Pb [138], Cd [139], aluminum chloride [140], polychlorinated biphenyls [141], TAA [142], CCl4 [143], D-gal [144], L-carnitine [145], LPS [146,147], palmitic acid [148], and aflatoxin B1 [149] Activating the Nrf2 pathway, promoting mitophagy, and suppressing the TLR4/NF-κB pathway [20,24,[150][151][152][153][154][155][156][157][158][159] CGA Neuronal cells and PC12 cells [34,191]; oligodendrocyte [196] and OL cell line M03-13…”