SUN-713 - Ethanol Drives Multi-Tissue Genomic Changes and Chrebp Activation in Mice

Introduction
Alcohol metabolism-induced reductive stress (elevated cytosolic NADH/NAD+) is directly linked to alcohol-related liver disease, affecting roughly 3–5% of the general population and over 50% of people with alcohol use disorder. Work in our laboratory has recently demonstrated that reductive stress activates Carbohydrate-response element binding protein (ChREBP) in the liver, contributing to the metabolic consequences of hepatic ethanol metabolism. While hepatic ChREBP activation by reductive stress is established, whether ethanol activates ChREBP across extrahepatic tissues remains unexplored. We sought to assess to what extent ethanol gavage activates ChREBP-mediated transcriptional targets across multiple tissues through NADH/NAD+ elevation, orchestrating systemic metabolic reprogramming contributing to early alcohol-induced metabolic dysfunction.
Methods
Male and female C57BL/6J mice (10 weeks old) received 5g/kg of ethanol gavage or water and were sacrificed 6 hours post-administration. Fifteen tissues were collected: liver, eWAT, scWAT, jejunum, ileum, brain, heart, kidney, lung, pancreas, spleen, stomach, testis, and ovaries. RNA sequencing was performed on all tissues, and tissue-specific transcriptomic signatures were generated and analyzed.
Results
Differential gene-expression analysis revealed clear, organ-specific transcriptomic signatures and identified liver, heart, kidney, ovaries, and spleen as tissues with pronounced ethanol-responsive changes. Cross-tissue correlation analysis identified liver, jejunum, kidney, ovaries/testis, and eWAT as prime candidates for ChREBP-mediated transcriptional responses based on coordinated patterns and shared metabolic pathway activation. Potential ChREBP activation in response to ethanol was evaluated by integrating Adh1 (NADH generator) with ChREBP expression (sensor). Tissues such as pancreas, brain and spleen showed low Adh1 and ChREBP expression, indicating minimal capacity for alcohol‑driven ChREBP activation. Heart, skeletal muscle, ileum and subcutaneous adipose tissue exhibited intermediate levels, whereas liver, jejunum/bowel, kidney, ovaries/testes and eWAT emerged as prime candidates in which ethanol‑induced NADH robustly engaged ChREBP‑dependent transcriptional targets. ChREBP target activation (Pklr, Fasn, Acly, Acaca) was validated by qPCR.
Conclusions
Ethanol induced transcriptomic remodeling across extra-hepatic tissues, highlighting an underappreciated systemic transcriptional response to alcohol exposure. ChREBP‑mediated transcriptional changes identify it as an important effector of multi‑organ responses to ethanol‑induced reductive stress. Collectively, these findings advance our understanding of early pathophysiological mechanisms in alcohol-related liver disease.

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