Role of the Pregnane X Receptor in Binge Ethanol-Induced Steatosis and Hepatotoxicity

Abstract

The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that defends against toxic agents. We have shown that PXR promotes chronic ethanol (EtOH)-induced steatosis. Therefore, we examined the role of PXR in binge EtOH-induced hepatotoxicity. Male wild type (WT) and Pxr-null mice were orally administered three binge doses of EtOH (4.5 g/kg, every 12 hours) and euthanized four hours after the final dose. Pxr-null mice displayed higher basal mRNA levels of hepatic lipogenic transcription factor sterol regulatory element binding protein 1c (Srebp-1c) and its target stearoyl-CoA desaturase 1 (Scd1) and the lipid peroxide detoxifying aldo-keto reductase 1b7 (Akr1b7) and higher protein levels of EtOH-metabolizing alcohol dehydrogenase 1 (ADH1). In both genotypes, binge EtOH-induced triglyceride accumulation was associated with inhibition of fatty acid β-oxidation and upregulation of Srebp-1c- regulated lipogenic genes and hepatic CYP2E1 protein. Unexpectedly, gene expression of Cyp2b10, a constitutive androstane receptor target gene, implicated in EtOH hepatotoxicity, was PXR-dependent upregulated by binge EtOH. Also, PXR-dependent was the binge EtOH-induced inhibition of hepatic Akr1b8 mRNA, and protein levels of aldehyde dehydrogenase (ALDH) 1A1 and anti-apoptotic Bcl-2, but increased pro-apoptotic Bax protein expression, leading to increases in residual EtOH concentration and the cellular oxidative stress marker, malondialdehyde. In contrast, Pxr-null mice displayed increased Akr1b7 gene and ADH1 protein expression and hypertriglyceridemia following binge EtOH exposure. Taken together, this study demonstrates that PXR ablation prevents EtOH induced upregulation of Cyp2b10 and that PXR potentiates binge EtOH-induced oxidative stress and inhibition of EtOH catabolism, but protects against alcoholic hyperlipidemia.

Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation

“…The centrilobular appearance of large fatty droplets is an early sign of steatosis onset, an outcome that was long attributed to boosted lipogenesis and suppression of lipid catabolism secondary to shifts in the redox state of the hepatic NAD/NADH pool[67]. Newer theories tend to attribute steatosis to transcriptional upregulation of various lipogenic genes driven by such ligand-responsive transcription factors as SREBP, PPAR α and PXR[68,69], or a suppression of the inhibitory effects of AMP-activated protein kinase upon acetyl CoA carboxylase activity, the rate-limiting enzyme in fatty acid synthesis[70].A novel alternative pro-steatotic mechanism emerged with growing knowledge of the role of toxic LDEs in ALD. Several factors increase the vulnerability of hepatocytes to LPO during ethanol exposure, including formation of reactive oxygen species via such routes as CYP2E1-catalysed ethanol oxidation; a shift in the mitochondrial NADH redox state; and the activation of NADPH19 oxidases within macrophages.…”

Metabolic Activation of Elemicin Leads to the Inhibition of Stearoyl-CoA Desaturase 1

“…As expected, the hepatic expression of the Scd1 mRNA and SCD1 protein were inhibited by elemicin and 1′-hydroxyelemicin. Downregulation of Scd1 was also observed in the binge ethanol-induced steatosis and hepatotoxicity . A previous study demonstrated that SCD1 deficiency may lead to hepatic overaccumulation of lipids in nonalcoholic fatty liver disease, indicating that TG accumulation might be induced by SCD1 inhibition.…”

“…Downregulation of Scd1was also observed in the binge ethanol-induced steatosis and hepatotoxicity. 34 A previous study demonstrated that SCD1 deficiency may lead to hepatic overaccumulation of lipids in nonalcoholic fatty liver disease, 24 indicating that TG accumulation might be induced by SCD1 inhibition. A previous study reported that the ratios of saturated-LPCs to monounsaturated-LPCs in mouse serum were decreased in the dextran sulfate sodium (DSS)-induced acute experimental colitis model, accompanied by Scd1 suppression.…”

Efavirenz and Efavirenz-like Compounds Activate Human, Murine, and Macaque Hepatic IRE1α-XBP1

“…6). Since lipid homeostasis has been shown previously to be differentially regulated in WT versus PXR-null mice (He et al, 2013;Choi et al, 2018), we also performed experiments to probe the impact of PXR on EFV-mediated lipid droplet formation. We observed no difference in lipid droplet formation in response to EFV between PXR-null and WT mouse hepatocytes (Fig.…”

“…PXR ablation has been shown to reduce high-fat dietinduced JNK-dependent cell death and lower levels of hepatic lipid accumulation in mice receiving a high-fat diet (He et al, 2013). On the other hand, PXR ablation shows no protective effect against ethanol-induced triglyceride formation and lipid droplet staining in mice, and higher basal levels of the lipid biosynthesis-activating transcription factor sterol regulatory element binding protein 1c (Srebp1c) (Choi et al, 2018). From this, it seems that PXR's involvement in lipid homeostasis and hepatotoxicity varies across stimuli.…”