Liver molecular networks associated with drinking behavior in nonhuman primates

Area of Science:

• Alcohol metabolism and addiction research
• Genetics and epigenetics of complex behaviors
• Nonhuman primate models for human disease

Background:

• Ethanol metabolism in the liver produces compounds affecting brain activity and drinking behavior.
• Alcohol consumption is highly heritable, with genetic variants influencing metabolism but explaining limited consumption variance.
• Hepatic molecular network variations may predict alcohol drinking behavior, even with uniform initial consumption.

Purpose of the Study:

• To investigate if hepatic molecular network variations predict alcohol drinking behavior in nonhuman primates.
• To identify molecular differences between light drinkers (LD) and very heavy drinkers (VHD) before behavioral divergence.
• To explore genetic and epigenetic contributions to alcohol consumption phenotypes.

Main Methods:

• Studied male rhesus macaques at baseline and during uniform alcohol consumption.
• Analyzed liver biopsies using multiomic and histologic methods after 3 months of uniform consumption.
• Compared molecular profiles of LD and VHD to identify differences predictive of drinking behavior.

Main Results:

• Hepatic molecular pathways and networks differed between LD and VHD at baseline and in response to identical alcohol consumption.
• Sirtuin Signaling and MYC-regulated networks were significantly enriched in both groups.
• Epigenomic mechanisms differed, with LD response via microRNAs and VHD via DNA methylation; no liver pathologies were observed.

Conclusions:

• Pre-existing molecular network differences suggest genetic contributions to drinking phenotypes.
• Differential molecular responses to alcohol indicate epigenetic mechanisms also influence drinking behavior development and progression.
• Findings highlight the interplay of genetics and epigenetics in shaping alcohol consumption in nonhuman primates.