Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis

Alcohol abuse is a global health problem causing a substantial fraction of chronic liver diseases. Abundant TGF-β—a potent pro-fibrogenic cytokine—leads to disease progression. Our aim was to elucidate the crosstalk of TGF-β and alcohol on hepatocytes. Primary murine hepatocytes were challenged with ethanol and TGF-β and cell fate was determined. Fluidigm RNA analyses revealed transcriptional effects that regulate survival and apoptosis. Mechanistic insights were derived from enzyme/pathway inhibition experiments and modulation of oxidative stress levels. To substantiate findings, animal model specimens and human liver tissue cultures were investigated. Results: On its own, ethanol had no effect on hepatocyte apoptosis, whereas TGF-β increased cell death. Combined treatment led to massive hepatocyte apoptosis, which could also be recapitulated in human HCC liver tissue treated ex vivo. Alcohol boosted the TGF-β pro-apoptotic gene signature. The underlying mechanism of pathway crosstalk involves SMAD and non-SMAD/AKT signaling. Blunting CYP2E1 and ADH activities did not prevent this effect, implying that it was not a consequence of alcohol metabolism. In line with this, the ethanol metabolite acetaldehyde did not mimic the effect and glutathione supplementation did not prevent the super-induction of cell death. In contrast, blocking GSK-3β activity, a downstream mediator of AKT signaling, rescued the strong apoptotic response triggered by ethanol and TGF-β. This study provides novel information on the crosstalk between ethanol and TGF-β. We give evidence that ethanol directly leads to a boost of TGF-β’s pro-apoptotic function in hepatocytes, which may have implications for patients with chronic alcoholic liver disease.© The Author(s) 201

Additional file 23 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 23: Table S15. Comparison of the sex-specific effects

Additional file 17 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 17: Table S9. PheWAS UKB-MVP meta-analysis results for each index lipid variant at Bonferroni threshold for multiple testing

Additional file 4 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 4: Table S3. Text mining results for the PoPS+ prioritized genes

Additional file 27 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 27: Table S17. Sex-stratified effect sizes in UK Biobank considering all individuals or only those not on cholesterol lowering medications

Additional file 8 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 8: Table S6. Association of lipid index variants with CAD, T2D and NAFLD

Additional file 10 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 10: Table S7. DESE phenotype-tissue association results using both GTEx gene-level and transcript-level selective expression

Additional file 2 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 2: Table S2. Association results for the multi-ancestry index SNPs with the gene prioritization

Additional file 5 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 5: Table S4. Frequency of lipid-related publications for the PoPS+ prioritized genes