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.
Highlights
The liver, the primary site of alcohol metabolism, is susceptible to many of the pharmacological ramifications of drinking, and rodent models of human consumption have been critical for elucidating these consequences
Several studies [4,5,6] and a large meta-analysis report [7] concluded that light to moderate alcohol consumption in humans (i.e. 30 g ethanol/d) is associated with a reduced risk of coronary heart disease and ischemic stroke, while heavier alcohol intake is linked to increased risk
With the foreknowledge that betweenspecies comparisons can be controversial, we suggest that the extent of freechoice alcohol drinking in P rats, with respect to the liver, ostensibly models low risk or nonhazardous alcohol drinking in humans
Summary
The liver, the primary site of alcohol metabolism, is susceptible to many of the pharmacological ramifications of drinking, and rodent models of human consumption have been critical for elucidating these consequences. The ethanolcontaining Lieber-DeCarli [1] and the Tsukamoto-French intragastric liquid diets [2] are widely accepted methods that produce maximal liver injury by forcefeeding rodents with ethanol. One prime example is the J- or U-shaped relationship between increasing alcohol consumption and the risk of atherosclerotic cardiovascular disease (not cardiomyopathy). Suggested mechanisms include a complex interaction between HDL and LDL cholesterol transfer dynamics in producing atherosclerosis, the potential deleterious effects of ethanol on the biology of atherosclerotic plaques, as well as oxidative stress, [8, 9]. Moderate alcohol consumption is inversely correlated with metabolic syndrome and diabetes mellitus in obese individuals, diabetes mellitus [10], as well as vascular dementia in the aging population [11]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call