Alcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function.
Chronic alcohol consumption affects the gene expression of a NAD-dependent deacetylase Sirtuis 1 (SIRT1) and the peroxisome proliferator-activated receptor-gamma coactivator1alpha (PGC-1alpha). Our aim was to verify that it also alters the forkhead (FoxO1) and p53 transcription factor proteins, critical in the hepatic response to oxidative stress and regulated by SIRT1 through its deacetylating capacity. Accordingly, rats were pair-fed the Lieber-DeCarli alcohol-containing liquid diets for 28 days. Alcohol increased hepatic mRNA expression of FoxO1 (p=0.003) and p53 (p=0.001) while corresponding protein levels remained unchanged. However phospho-FoxO1 and phospho-Akt (protein kinase) were both decreased by alcohol consumption (p=0.04 and p=0.02, respectively) while hepatic p53 was found hyperacetylated (p=0.017). Furthermore, mitochondrial SIRT5 was reduced (p=0.0025), and PGC-1alpha hyperacetylated (p=0.027), establishing their role in protein modification. Thus, alcohol consumption disrupts nuclear-mitochondrial interactions by post-translation protein modifications, which contribute to alteration of mitochondrial biogenesis through the newly discovered reduction of SIRT5.
Section of Liver Disease and Nutrition, James J. Peters VA Medical Center, 130 West Kingsbridge Road (151-2), Bronx, NY 10468, USA. liebercs@aol.com
Charles S
CS
Lieber
Maria Anna
MA
Leo
Xiaolei
X
Wang
Leonore M
LM
Decarli
D000107:Acetylation / Q000187:drug effects; D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000633:toxicity*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
D000431:Ethanol; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D056564:Sirtuin 1; D037761:Sirtuins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C501429:Ppargc1a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C530376:SIRT5 protein, rat; C488368:Sirt1 protein, rat