The Chemical Chaperone 4‐Phenylbutyric Acid Prevents Alcohol‐Induced Liver Injury in Obese KK‐Ay Mice

Background Co‐occurrence of metabolic syndrome and chronic alcohol consumption is increasing worldwide. The present study investigated the effect of the chemical chaperone 4‐phenylbutyric acid (PBA)—which has been shown to alleviate dietary steatohepatitis caused by endoplasmic reticulum (ER) stress—on chronic‐plus‐binge ethanol (EtOH)–induced liver injury in a mouse model of obesity. Methods Male KK‐Ay mice (8 weeks old) were fed a Lieber–DeCarli diet (5% EtOH) for 10 days. Some mice were given PBA intraperitoneally (120 mg/kg body weight, daily) during the experimental period. On day 11, mice were gavaged with a single dose of EtOH (4 g/kg body weight). Control mice were given a dextrin gavage after being pair‐fed a control diet. All mice were then serially euthanized before or at 9 hours after gavage. Results Chronic‐plus‐binge EtOH intake induced massive hepatic steatosis along with hepatocyte apoptosis and inflammation, which was reversed by PBA treatment. Administration of PBA also suppressed chronic‐plus‐binge EtOH–induced up‐regulation of ER stress‐related genes including binding immunoglobulin protein (Bip), unspliced and spliced forms of X‐box‐binding protein‐1 (uXBP1 and sXBP1, respectively), inositol trisphosphate receptor (IP3R), and C/EBP homologous protein (CHOP). Further, it blocked chronic‐plus‐binge EtOH–induced expression of the oxidative stress marker heme oxygenase‐1 (HO‐1) and 4‐hydroxynonenal. Chronic EtOH alone (without binge) increased Bip and uXBP1, but it did not affect those of sXBP1, IP3R, CHOP, or HO‐1. PBA reversed the prebinge expression of these genes to control levels, but it did not affect chronic EtOH‐induced hepatic activity of cytochrome P450 2E1. Conclusions Binge EtOH intake after chronic consumption induces massive ER stress‐related oxidative stress and liver injury in a mouse model of obesity through dysregulation of the unfolded protein response. PBA ameliorated chronic‐plus‐binge EtOH–induced liver injury by reducing ER and oxidative stress after an EtOH binge. Chronic‐plus‐binge ethanol (EtOH) feeding induced severe hepatic steatosis with hepatocyte apoptosis in obese KK‐Ay mice through dysregulation of the unfolded protein response. The treatment with 4‐phenylbutyrate (PBA) ameliorated chronic‐plus‐binge EtOH‐induced liver injury by reducing ER and oxidative stress after an EtOH binge (A: immunohistological staining for ccCK18, scale bar = 100 μm, B‐D: RT‐PCR for sXBP1, CHOP, or HO‐1). The components of ER stre