4-OI Attenuates Carbon Tetrachloride-Induced Hepatic Injury via Regulating Oxidative Stress and the Inflammatory Response

Abstract

The liver is an important metabolic organ, and acute liver injury (ALI) is potentially lethal. Itaconate, a metabolic intermediate from the tricarboxylic acid cycle, showed emerging anti-oxidative and anti-inflammation properties, and an accumulating protective effect in multiple diseases, but its role in ALI still needs to be further explored. Here we established an ALI model induced by carbon tetrachloride in mice. Our results showed that 4-Octyl itaconate (OI), a derivate of itaconate, mitigated hepatic damage by improving liver function, reducing histopathological damage, and decreasing the death of hepatocytes. Additionally, OI decreased myeloperoxidase and thiobarbituric acid reactive substances (TBARS) levels in the ALI model. OI also inhibited the inflammatory response by reducing pro-inflammatory cytokine secretion (IL-6, TNF-α, IL-1β, and MCP-1) and infiltration of macrophages and neutrophils in the ALI model. However, administration of ML385, a specified Nrf2 inhibitor, eliminated the protective properties of OI in the CCl4-induced liver injury model by increasing hepatic damage and oxidative stress. Furthermore, OI increased the expression and nuclear translocation of Nrf2 and elevated the expression of heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1, while knockdown of Nrf2 eliminated these effects in murine hepatocyte NCTC 1469 under CCl4 treatment. Moreover, we found that OI reduced serum High-mobility group box 1 (HMGB1) levels in CCl4-treated mice. Finally, OI inhibited nuclear translocation of factor-kappa B (NF-𝜅B) and inflammatory cytokine production in murine macrophages. In conclusion, these results indicated that OI ameliorated CCl4-induced ALI by mitigating oxidative stress and the inflammatory response. The possible mechanism was associated with the elevation of Nrf2 nuclear translocation and inhibition of HMGB1 mediated the nuclear translocation of NF-𝜅B.

Protective Role of 4‐Octyl Itaconate in Murine LPS/D‐GalN‐Induced Acute Liver Failure via Inhibiting Inflammation, Oxidative Stress, and Apoptosis

“…Additionally, OI, a derivate of itaconate, showed a protective effect in the hepatic ischemia-reperfusion injury murine model [ 12 ]. Moreover, our previous publication showed that OI protected mice from carbon tetrachloride-induced hepatic injury [ 22 ]. Nonetheless, the mechanism of liver injury is different in different pathogenic models.…”

“…RAW264.7 and NCTC 1469 were grown in 6-well plates to 40-50% confluent. Then, 50 nM Nrf2 siRNA or control siRNA was transfected with Lipofectamine 6000 as we reported before [ 22 ]. The cells were used for the next experiments 48 h after transfection.…”

Hepatoprotective Role of 4-Octyl Itaconate in Concanavalin A-Induced Autoimmune Hepatitis

“…Previous studies have confirmed that Nrf2 activation played an important role in alleviating liver injury [23,24]. For example, we previously found that Nrf2 activation mitigated carbon tetrachloride-induced hepatic injury by inhibiting oxidative stress and inflammation [24]. Furthermore, OI mitigated ischemia-reperfusion injury-induced liver injury by activating the Nrf2 pathway [25].…”

“…Moreover, Nrf2 was recently found to bind with the promoter regions of some proinflammatory cytokines such as interlukin-6 (IL-6) and directly inhibit their transcription to alleviate the inflammatory response [22]. Previous studies have confirmed that Nrf2 activation played an important role in alleviating liver injury [23,24]. For example, we previously found that Nrf2 activation mitigated carbon tetrachloride-induced hepatic injury by inhibiting oxidative stress and inflammation [24].…”

Four-Octyl Itaconate Attenuates UVB-Induced Melanocytes and Keratinocytes Apoptosis by Nrf2 Activation-Dependent ROS Inhibition

“…Normally, Nrf2 is combined with Kelch-like ECH-associated protein 1 (Keap1) to form a complex. Oxidative injury and other stress conditions could lead to keap1-Nrf2 dissociation [15]. Then, Nrf2 translocate from the cytoplasm into the nucleus and activate antioxidative genes such as heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), which could generate cytoprotective effects [16].…”