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

Abstract

Alcohol consumption exacerbates alcoholic liver disease by attenuating the activity of AMP-activated protein kinase (AMPK). AMPK is activated by fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, and inhibited by direct interaction with cereblon (CRBN), a component of an E3 ubiquitin ligase complex. Based on these preliminary findings, we investigated that CRBN would be up-regulated in the liver by alcohol consumption and that CRBN deficiency would ameliorate hepatic steatosis and pro-inflammatory responses in alcohol-fed mice by increasing AMPK activity. Wild-type, CRBN and PPARα null mice were fed an alcohol-containing liquid diet and administered with fenofibrate. Gene expression profiles and metabolic changes were measured in the liver and blood of these mice. Expression of CRBN, cytochrome P450 2E1 (CYP2E1), lipogenic genes, pro-inflammatory cytokines, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were increased in the Lieber-DeCarli alcohol-challenged mice. Fenofibrate attenuated the induction of CRBN and reduced hepatic steatosis and pro-inflammatory markers in these mice. Ablation of the gene encoding CRBN produced the same effect as fenofibrate. The increase in CRBN gene expression by alcohol and the reduction of CRBN expression by fenofibrate were negated in PPARα null mice. Fenofibrate increased the recruitment of PPARα on CRBN gene promoter in WT mice but not in PPARα null mice. Silencing of AMPK prevented the beneficial effects of fenofibrate. These results demonstrate that activation of PPARα by fenofibrate alleviates alcohol-induced hepatic steatosis and inflammation by reducing the inhibition of AMPK by CRBN. CRBN is a potential therapeutic target for the alcoholic liver disease.

Cereblon in health and disease

“…For instance, a HFD increases CRBN expression at gene and protein levels [43], suggesting that intracellular energy balance is an important regulator of CRBN expression. Another study shows that fenofibrate, a PPARα agonist, attenuates alcohol-induced CRBN overexpression and liver disease [33]. In this study, alcohol treatment increased CRBN gene expression by suppressing the PPARα-dependent pathway, suggesting that PPARα is a negative transcriptional regulator of CRBN.…”

“…Whereas a HFD enhances lipogenesis and gluconeogenesis in mice with elevated CRBN levels, CRBN KO suppresses HFD-induced lipogenesis and gluconeogenesis. Another recent study demonstrates that CRBNdeficient mice are resistant to alcohol-induced metabolic dysfunction via peroxisome proliferator-activated receptor alpha (PPARα)/AMPK pathway activation [33], suggesting a regulatory role of CRBN in pathological metabolic remodeling of the liver.…”

Induction of SIRT1 by melatonin improves alcohol‐mediated oxidative liver injury by disrupting the CRBN‐YY1‐CYP2E1 signaling pathway

“…Previous studies have shown that CRBN has a significant role in the regulation of metabolic homeostasis and metabolic processes. 22,23 Therefore, we examined the potential role of CRBN in alcohol-mediated regulation of oxidative stress and liver injury using an adenoviral delivery system (Ad-Crbn) and Crbn null mice. Quantitative PCR analysis showed that Ad-Crbn was successfully delivered in mouse livers.…”

“…It is highly expressed in the brain and is also present in diverse tissues, including skeletal muscle, kidney, and liver . Our previous studies have demonstrated that disruption of CRBN improves hepatic steatosis and inflammation via AMPK activation in mouse models of nonalcoholic and alcoholic fatty liver diseases . In addition, Ying Yang 1 (YY1) is a multifunctional zinc‐finger transcription factor of the polycomb protein family which can bind to its signature binding motif (CCATNTT) .…”

“…20,21 Our previous studies have demonstrated that disruption of CRBN improves hepatic steatosis and inflammation via AMPK activation in mouse models of nonalcoholic and alcoholic fatty liver diseases. 22,23 In addition, Ying Yang 1 (YY1) is a multifunctional zinc-finger transcription factor of the polycomb protein family which can bind to its signature binding motif (CCATNTT). 24 YY1 plays an important role in the control of multiple pathologies, including cancer, diabetes, and obesity.…”