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.

Effects of Moderate Ethanol Consumption on Lipid Metabolism and Inflammation Through Regulation of Gene Expression in Rats

“…The reduction in serum cholesterol and hepatic cholesterol observed in this study may be mechanistically related to a reduction in Hmgcr and Srebp-2 gene expression. HMG-CoA reductase (Hmgcr) is a key rate-limiting enzyme in cholesterol synthesis (Yin et al, 2009;Klein et al, 2014), while Srebp-2 is the primary transcription factor that regulates the expression of Hmgcr (Sakakura et al, 2001;Yin et al, 2009;Wang et al, 2010). The current findings concur with a prior study demonstrating that moderate ethanol consumption decreases hepatic Hmgcr gene expression in alcoholpreferring rats consuming ethanol daily (Klein et al, 2014).…”

“…Cardiovascular diseases (CVDs), namely, coronary artery disease and ischemic stroke, hypertension and atrial fibrillation have close associations with chronic high alcohol consumption. An increasing body of evidence continues to validate a J-or U-shaped correlation between alcohol consumption and CVD risk factors (Carnevale and Nocella, 2012;Bergmann et al, 2013;Chiva-Blanch et al, 2013;Wakabayashi, 2013a;Klein et al, 2014;Matsumoto et al, 2014;O'Keefe et al, 2014). This J-or U-shaped correlation indicates potential cardioprotective effects of light-to-moderate alcohol consumption, while high levels of consumption confer increased risk (Krenz and Korthuis, 2012).…”

Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats

“…Eight additional genes in the cholesterol pathway expression decreased by 1.3‐ to 1.5‐fold. Alcohol consumption by P rats also decreased the expression of cholesterol synthesis genes in the liver (Klein et al., ). Cholesterol is important for brain function, playing a major role in synaptogenesis, membranes, synaptic vesicles, and myelin sheaths; 70 to 80% of the cholesterol in the brain is in the myelin sheaths.…”

Characterization of Postprandial Effects on CSF Metabolomics: A Pilot Study with Parallel Comparison to Plasma

“…Fourth, in the present study, we did not control the subjects' alcohol and food habits that might have affected the postprandial responses of metabolites. Alcohol intake, as well as a high fat diet, has been well demonstrated to cause alterations of expressions of various hepatic genes, including genes related to energy homeostasis and diet metabolism [33][34][35], and that might result in an altered postprandial response. Last, lumbar puncture is an invasive approach and has been reported to increase the levels of several hormones in plasma [36].…”