Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis

Abstract

Background The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. Method The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. Results The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase -1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-Nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. Conclusions Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol–induced fatty liver in mice. General significance The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study.

Glycycoumarin ameliorates alcohol-induced hepatotoxicity via activation of Nrf2 and autophagy

“…Nrf2 is a key player of cellular antioxidant defense system. The protective role of Nrf2 in alcohol-induced hepatoxicity is well established (16)(17)(18). Regarding the mechanisms underlying hepatoprotective effect of GCM, ours data showed that GCM p62, also known as Sequestosome-1, is a substrate of autophagy (30).…”

“…It has been shown that activation of Nrf2 plays a critical role in protection against alcohol-induced liver injury (16)(17)(18). We hypothesized that regulation of Nrf2 pathway might be involved in the hepatoprotective effect of GCM.…”

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“…Activation of Nrf2 signaling mainly by low molecular weight molecules has drawn significant attention in the past few years (Zhou et al 2014). Following its absorption, SFN undergoes conjugation to GSH, enhancing intracellular SFN accumulation, generating intracellular stress in turn, activating various signaling pathways including kelch-like ECH-associated protein 1 (Keap1)-Nrf2 (Hayes et al 2010;Wang et al 2015).…”

Demethyleneberberine, a Natural Mitochondria-Targeted Antioxidant, Inhibits Mitochondrial Dysfunction, Oxidative Stress, and Steatosis in Alcoholic Liver Disease Mouse Model

“…The dosages were based on preliminary range-finding studies. All animals were exposed to ethanol (6 g/kg orally gavage) for three times at 12-hour intervals, whereas mice in the control group received saline as a vehicle control (Zhou et al, 2014). Mice were treated with DMB 1 hour after each ethanol exposure, whereas other groups received an equal volume of vehicle.…”