title: A snapshot of the hepatic transcriptome: ad libitum alcohol intake suppresses expression of cholesterol synthesis genes in alcohol-preferring (P) rats.
abstract: Research is uncovering the genetic and biochemical effects of consuming large quantities of alcohol. One prime example is the J- or U-shaped relationship between the levels of alcohol consumption and the risk of atherosclerotic cardiovascular disease. Moderate alcohol consumption in humans (about 30 g ethanol/d) is associated with reduced risk of coronary heart disease, while abstinence and heavier alcohol intake is linked to increased risk. However, the hepatic consequences of moderate alcohol drinking are largely unknown. Previous data from alcohol-preferring (P) rats showed that chronic consumption does not produce significant hepatic steatosis in this well-established model. Therefore, free-choice alcohol drinking in P rats may mimic low risk or nonhazardous drinking in humans, and chronic exposure in P animals can illuminate the molecular underpinnings of free-choice drinking in the liver. To address this gap, we captured the global, steady-state liver transcriptome following a 23 week free-choice, moderate alcohol consumption regimen (∼ 7.43 g ethanol/kg/day) in inbred alcohol-preferring (iP10a) rats. Chronic consumption led to down-regulation of nine genes in the cholesterol biosynthesis pathway, including HMG-CoA reductase, the rate-limiting step for cholesterol synthesis. These findings corroborate our phenotypic analyses, which indicate that this paradigm produced animals whose hepatic triglyceride levels, cholesterol levels and liver histology were indistinguishable from controls. These findings explain, at least in part, the J- or U-shaped relationship between cardiovascular risk and alcohol intake, and provide outstanding candidates for future studies aimed at understanding the mechanisms that underlie the salutary cardiovascular benefits of chronic low risk and nonhazardous alcohol intake.
authors.affiliation: Purdue University Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, IN, United States of America; Department of Animal Science, Purdue University, West Lafayette, IN, United States of America.
authors.forename: Jonathon D
authors.initials: JD
authors.lastname: Klein
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN, United States of America.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Sherrill
authors.affiliation: Department of Animal Science, Purdue University, West Lafayette, IN, United States of America.
authors.forename: Gabriella M
authors.initials: GM
authors.lastname: Morello
authors.affiliation: Core Facility, Purdue University, West Lafayette, IN, United States of America; Department of Horticulture and Landscape Architecture, Purdue University, West Lafayette, IN, United States of America.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: San Miguel
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Suthat
authors.initials: S
authors.lastname: Liangpunsakul
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Tiebing
authors.initials: T
authors.lastname: Liang
authors.affiliation: Purdue University Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, IN, United States of America; Department of Animal Science, Purdue University, West Lafayette, IN, United States of America; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Muir
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lumeng
authors.affiliation: Purdue University Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, IN, United States of America; Department of Animal Science, Purdue University, West Lafayette, IN, United States of America; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Lossie
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics*; D000428:Alcohol Drinking / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal; D002755:Choice Behavior; D002784:Cholesterol / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008969:Molecular Sequence Data; D051381:Rats; D017423:Sequence Analysis, RNA / Q000379:methods
chemical_list: D000214:Acyl Coenzyme A; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D000431:Ethanol; D002784:Cholesterol