Alcohol Preference Impacts Multi-Organ Transcriptome in MetALD

Area of Science:

• Metabolic dysfunction
• Alcohol use disorder (AUD)
• Liver disease

Background:

• Alcohol use disorder (AUD) presents significant public health challenges with increasing global prevalence and metabolic consequences.
• Existing models inadequately represent AUD, especially when combined with excessive caloric intake.
• Metabolic dysfunction-associated steatotic liver disease with increased alcohol intake (MetALD) is a recently characterized condition differentiating alcohol-related liver issues.

Purpose of the Study:

• To investigate metabolic phenotypes and gene expression alterations in a mouse model of MetALD.
• To differentiate metabolic profiles based on alcohol preference, using blood phosphatidylethanol levels and consumption data.
• To identify potential molecular biomarkers associated with alcohol preference in MetALD.

Main Methods:

• Mice were subjected to high-fat and chow diets with 10% ethanol (EtOH) for 13 weeks.
• mRNA sequencing was conducted on brain, liver, skeletal muscle, ileum, and white adipose tissue.
• Gut microbiome diversity was assessed using 16S sequencing.

Main Results:

• Alcohol-preferring mice showed reduced glucagon but no significant differences in dyslipidemia or hepatic steatosis.
• Reduced gut microbiome diversity, Wnt signaling, and elevated acute-phase response genes were observed in the ileum.
• Decreased Wnt and Hippo signaling in the brain and liver, respectively, alongside increased neural inflammation and adipose mitochondrial translation were noted. Specific gene expression changes (Nek3, Ntf3, Cux1, Irf6) were identified as potential biomarkers.

Conclusions:

• The developed MetALD mouse model aids future research into intervention strategies.
• The study identified potential biomarkers for alcohol preference, offering new avenues for understanding AUD.
• This research contributes to differentiating metabolic consequences of alcohol intake and hypercaloric diets.