Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation

Abstract

Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is derivative of ω-3 docosahexaenoic acid (DHA), which has been shown to have pro-resolutive and anti-inflammatory effects. We tested the hypothesis that the application of MaR1 could prevent the development of fibrosis in an animal model of chronic hepatic damage. Sprague-Dawley rats were induced with liver fibrosis by injections of diethylnitrosamine (DEN) and treated with or without MaR1 for four weeks. In the MaR1-treated animals, levels of AST and ALT were normalized in comparison with DEN alone, the hepatic architecture was improved, and inflammation and necrotic areas were reduced. Cell proliferation, assessed by the mitotic activity index and the expression of Ki-67, was increased in the MaR1-treated group. MaR1 attenuated liver fibrosis and oxidative stress was induced by DEN. Plasma levels of the pro-inflammatory mediators TNF-α and IL-1β were reduced in MaR1-treated animals, whereas the levels of IL-10, an anti-inflammatory cytokine, increased. Interestingly, MaR1 inhibited the translocation of the p65 subunit of NF-κB, while increasing the activation of Nrf2, a key regulator of the antioxidant response. Finally, MaR1 treatment reduced the levels of the pro-fibrotic mediator TGF-β and its receptor, while normalizing the hepatic levels of IGF-1, a proliferative agent. Taken together, these results suggest that MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and decreasing oxidative stress and inflammation. These results open the possibility of MaR1 as a potential therapeutic agent in fibrosis and other liver pathologies.

Maresin1 Ameliorates Sepsis-Induced Microglial Neuritis Induced through Blocking TLR4-NF-κ B-NLRP3 Signaling Pathway

“…Previous studies indicated that activated microglia can damage neurogenesis and are mainly associated with cognitive and mood dysfunctions [ 41 ]. Maresin1 (MaR1), a newly identified metabolite of 22-carbon hexaenoic acid (DHA) derived from macrophages, displays anti-inflammatory and pro-inflammatory effects [ 42 ]. Notably, MaR1 has been demonstrated to significantly inhibit macrophage infiltration and inflammation in the hippocampus.…”

Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development

“…In cultured hepatocytes, RvD1 also inhibits hepatocyte proliferation and is implicated in attenuating cancer growth ( Lu et al, 2018b ). Consistently, both RvD and RvE prevent the progression to cancer ( Kuang et al, 2016 ; Rodriguez et al, 2020 ) and MaR treatment mitigated fibrosis induced by DEN ( Rodriguez et al, 2021 ). Again, the AKT-mTOR regulated autophagy in HSC contributes to the RvD inhibited fibrosis ( Li et al, 2021 ).…”

An update on animal models of liver fibrosis

“…Furthermore, DEN administration results in excessive deposition of ECM protein (collagen) in rat liver and seems appropriate to study early events associated with the development of liver fibrosis (45). Some studies induced liver fibrosis by intraperitoneal injection of DEN in rats once a week for 4-6 weeks (46,47). DEN, a known carcinogen that leads to significant oxidative stress and DNA mutations, enhances lipotoxicity and accelerates the progression of fibrosis and cirrhosis, has long been used in hepatocellular carcinoma (HCC) models (48).…”