Estrogen-related receptor γ controls hepatic CB₁receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol

Abstract

Background The hepatic endocannabinoid system and cytochrome P450 2E1 (CYP2E1), a key enzyme causing alcohol-induced reactive oxygen species (ROS) generation, are major contributors to the pathogenesis of alcoholic liver disease. The nuclear hormone receptor oestrogen-related receptor γ (ERRγ) is a constitutively active transcriptional activator regulating gene expression. Objective To investigate the role of ERRγ in the alcohol-mediated regulation of CYP2E1 and to examine the possibility to control alcohol-mediated oxidative stress and liver injury through an ERRγ inverse agonist. Design For chronic alcoholic hepatosteatosis study, C57BL/6J wild-type and CB1−/− mice were administered alcohol for 4 weeks. GSK5182 and chlormethiazole (CMZ) were given by oral gavage for the last 2 weeks of alcohol feeding. Gene expression profiles and biochemical assays were performed using the liver or blood of mice. Results Hepatic ERRγ gene expression induced by alcohol-mediated activation of CB1 receptor results in induction of CYP2E1, while liver-specific ablation of ERRγ gene expression blocks alcohol-induced expression of CYP2E1 in mouse liver. An ERRγ inverse agonist significantly ameliorates chronic alcohol-induced liver injury in mice through inhibition of CYP2E1-mediated generation of ROS, while inhibition of CYP2E1 by CMZ abrogates the beneficial effects of the inverse agonist. Finally, chronic alcohol-mediated ERRγ and CYP2E1 gene expression, ROS generation and liver injury in normal mice were nearly abolished in CB1−/− mice. Conclusions ERRγ, as a previously unrecognised transcriptional regulator of hepatic CB1 receptor, controls alcohol-induced oxidative stress and liver injury through CYP2E1 induction, and its inverse agonist could ameliorate oxidative liver injury due to chronic alcohol exposure.

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

“…[48] Given that CYP2E1 gene expression is under the transcriptional control of factors responsive to inflammation [19,29,49,50] it was theorized that inhibition of glycolysis in breast cancer cells bearing diverse genetic background would lead to alternative CYP2E1 cellular levels and hence dissimilar ROS. [42] On the other side inhibition of glycolysis would lead to increased ROS generation [31] that could be altered by CYP2E1 enzymatic activity.…”

Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK

“…For chronic alcoholic liver injury challenge, WT and CRBN null mice, weighing 20-30 g at 8 weeks of age were divided into 3 groups: 1) the control liquid diet in which alcohol was substituted isocalorically with maltose dextrin gavage for 4 weeks (n = 5), 2) Lieber-DeCarli alcohol liquid diet (Research Diets, New Brunswick, NJ, USA) with 5% alcohol (36% alcohol-contained calories) gavage for 4 weeks (n = 7), and 3) Lieber-DeCarli alcohol liquid diet-treated with daily fenofibrate (Sigma-Aldrich, St. Louis, MO, USA, 100 mg/kg body weight) gavage for last 2 weeks (n = 8), as described previously [20]. In some experiments, WT and PPARα null mice were fed with the Lieber-DeCarli alcohol liquid diet with or without 5% alcohol for 4 weeks (n = 5-8/group).…”

“…Total RNA, isolated by TRIzol reagent (Invitrogen), in accordance with the manufacturer's instructions, was used for qPCR analysis as described previously [13,16,20,23,25]. cDNA was synthesized using the Maxima® First Strand cDNA Synthesis kit (Fermentas, Vilnius, Lithuania).…”

O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor γ Promotes Hepatic Gluconeogenesis

“…ERRγ plays an important role in the regulation of glucose, lipid, alcohol and iron metabolism in mouse liver [16], [17]. Hepatic ERRγ expression is induced in fasting and the diabetic state, and causes insulin resistance and glucose intolerance [18].…”