Abstract The conjugation of neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to target proteins, termed neddylation, participates in many cellular processes and is aberrant in various pathological diseases. Its relevance to liver function and failure remains poorly understood. Herein, we show dysregulated expression of NAE1, a regulatory subunit of the only NEDD8 E1 enzyme, in human acute liver failure. Embryonic- and adult-onset deletion of NAE1 in hepatocytes causes hepatocyte death, inflammation, and fibrosis, culminating in fatal liver injury in mice. Hepatic neddylation deficiency triggers oxidative stress, mitochondrial dysfunction, and hepatocyte reprogramming, potentiating liver injury. Importantly, NF-κB-inducing kinase (NIK), a serine/Thr kinase, is a neddylation substrate. Neddylation of NIK promotes its ubiquitination and degradation. Inhibition of neddylation conversely causes aberrant NIK activation, accentuating hepatocyte damage and inflammation. Administration of N-acetylcysteine, a glutathione surrogate and antioxidant, mitigates liver failure caused by hepatic NAE1 deletion in adult male mice. Therefore, hepatic neddylation is important in maintaining postnatal and adult liver homeostasis, and the identified neddylation targets/pathways provide insights into therapeutically intervening acute liver failure.
Drug-induced liver injury Drug-induced liver injury (DILI) refers to the direct or indirect damage caused by drugs or their metabolites to the liver. It is one of the major adverse reactions of drugs, and also an important factor limiting the development of new drugs. DILI has been reported frequently, but the most representative ones are still non-specific drugs that need to be taken for a long time, such as efavirenz (an antiviral drug used to treat AIDS), rifampicin (an antimicrobial drug used to treat tuberculosis) and the common and classic antipyretic analgesic acetaminophen.
A growing literature suggests that the non-nucleoside analog reverse transcriptase inhibitor efavirenz can induce significant upregulation of CHOP and GRP78 mRNA and protein levels, phosphorylation of eIF2α, production of XBP1s, and expansion of ER membrane in primary human hepatocytes [88, 89]. Besides, the anti-tuberculosis drug rifampicin can increase the mRNA and protein expression levels of GRP78, PERK, ATF4, and CHOP in LO2 and HepG2, resulting in apoptosis, suggesting that it may induce DILI through ERS pathway [90]. Acetaminophen, a classic antipyretic and analgesic drug, can also induce glutathione depletion in mouse hepatocytes, causing redox imbalance in the lumen, accelerating the phosphorylation of eIF2α, activation of ATF6 and CHOP, and ultimately inducing hepatocyte apoptosis and liver injury by ERS [91]. In addition, Kusama H et al. found that intraperitoneal injection of acetaminophen in mice can cause extensive apoptosis or necrosis of mouse hepatocytes and increased level of ATF6 mRNA, suggesting that acetaminophen-induced hepatotoxicity may also be related to the activation of the ATF6 pathway [92]. In addition to the drugs mentioned above, liver injury caused by traditional herbal medicines remains an important concern. Fructus Cnidium can induce apoptosis by activating ERS and inhibiting the proliferation of LO2 cells [93]. Oxymatrine in Sophora flavescens can also induce the occurrence of ERS and the phosphorylation of c-JNK through the excessive accumulation of reactive oxygen species, causing LO2 apoptosis, which can be alleviated by 4-PBA [94]. In vivo studies found that psoralen induces ERS in hepatocytes of female C57 mice, increases liver injury-related factors’ expression, and causes inflammatory infiltration and vacuolar degeneration in hepatocytes [95]. The mechanism of DILI is indeed very complex, involving various mechanisms such as protein dysfunction, inflammation, oxidative stress, mitochondrial damage, and autoimmune response. However, overwhelming evidence suggests that ERS is also an important mechanism causing DILI.
Endoplasmic reticulum stress-mediated cell death in liver injury
Cell Death & Disease - Endoplasmic reticulum stress-mediated cell death in liver injury