The transcription factor X-box binding protein 1 (XBP1) plays critical roles in the immune system. For example, XBP1 is required for plasma cell development and can disrupt proper function of tumor-associated dendritic cells. A number of post-transcriptional mechanisms regulate XBP1, but a complete understanding of the processes that govern its expression and activity in distinct situations is lacking. The active form of XBP1, termed XBP1s, is dependent upon cytoplasmic splicing of Xbp1 mRNA by IRE1, a transmembrane endoribonuclease/kinase positioned in the endoplasmic reticulum (ER) membrane. IRE1 is a key signal transducer in the cellular response to ER stress, also known as the unfolded protein response (UPR). The IRE1-XBP1 pathway coordinates a broad program of gene transcription that promotes functions of the secretory pathway and alters various aspects of lipid homeostasis under conditions that perturb the ER environment and/or increase demand on its protein folding capacity. ER stress also activates the UPR signal transducer PERK, an ER transmembrane kinase that mediates efficient repression of protein synthesis. Previous studies have shown that microRNA(miR)-214 can negatively regulate XBP1 expression and is down-regulated during ER stress. Using PERK-deficient mouse embryo fibroblasts, we have found that ER stress-mediated diminishment of miR-214 is partially dependent on the PERK pathway, suggesting a novel mechanism of regulatory crosstalk between the PERK and IRE1-XBP1 branches of the UPR. The significance of miR-214 in the cellular response to ER stress and to XBP1-mediated events is under investigation.

Poor nutrition and alcohol intake are leading environmental factors associated with morbidity and mortality worldwide. However, the physiological interactions between poor diet and excessive alcohol intake remain unclear. Prior research from our lab showed diet significantly influenced measures of kidney and liver function in mice exposed to alcohol for 3 weeks. However, it was unclear whether the effects were due to diet, chronic alcohol consumption, or an additive effect of both. All experiments were performed in accordance with protocols approved by the Liberty University IACUC and conform to the FASEB standards for the use of animals in research and education. Weanling (3‐week old) male mice from the C57Bl/6 strain were purchased from The Jackson Laboratory and acclimated to a standard chow diet and housing for 7 days. Mice were then given ad libitum access to 1 of 3 diets: 1) standard laboratory chow, 2) a commercially available Western Diet (WD), or 3) a novel Americanized diet (AD). The AD was formulated to match the 50th percentile of intake for sodium, potassium, simple sugars, phosphorus, and fiber as reported in the recent What we eat in America report, based on 2011–2012 NHANES data. After 6 weeks on their assigned diet, each dietary group received distilled water or 10% (volume) ethanol solution as their only source of drinking water for an additional 4 weeks. Body weights and beverage consumption were recorded each week throughout the study. Systolic blood pressure was recorded at baseline and after 4 weeks of ethanol exposure. Following 4 weeks of ethanol intake, renal blood flow was estimated using contrast‐enhanced ultrasonography, and the mice were euthanized and kidney and liver tissues were processed for histology and quantitative real‐time RT‐PCR analysis of gene expression. All data were analyzed using general linear models in SPSS. Diet significantly influenced body weight, with both the WD and AD fed mice having a similarly (p=0.1) greater body weight as compared to mice fed chow (p<0.01). However, alcohol had no additional effect on weight gain (p=0.1). Consistent with previous findings, mice fed chow had the highest daily consumption of alcohol that was greater (p=0.05) than mice fed the WD, but not mice fed the AD (p=0.8). Histological analysis revealed hepatic steatosis in mice fed the WD and AD, and this did not appear to be worsened by alcohol intake. Although there was no difference in systolic blood pressure between the groups, mice fed the AD had a significant reduction in estimated renal blood flow as compared to mice fed WD (p=0.01) and chow (p<0.001). Interestingly, ethanol consumption caused a 25% increase in estimated renal medullary flow. Preliminary data indicate that genes (Hspa5 and Hsp90b1) associated with the cellular response to stress in the endoplasmic reticulum (ER) were expressed at higher levels in livers of mice fed the WD and AD, and this apparent ER stress was not exacerbated by alcohol intake. Taken together, the results from this study suggest that diet and alcohol significantly influence liver and renal health in mice, with a majority of the pathophysiology caused by diet.Support or Funding InformationProject was funded by LUCOM Intramural Grant #2018‐01.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.