Influence of sex and liver cirrhosis on the expression of miR-146a-5p and its target genes, IRAK1 and TRAF6

• Published in: Brain research 2024-03, Vol.1827, p.148763-148763, Article 148763
• Main Authors: Naidu, Carol, Cox, Amanda J., Lewohl, Joanne M.
• Format: Article
• Language: English
• Subjects: Alcoholism - genetics; Expression; Female; Human; Humans; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - metabolism; Liver Cirrhosis - genetics; Male; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Prefrontal cortex; Regulation; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - metabolism
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2024.148763

[Display omitted] •Severity of alcohol use disorder, concomitant liver pathology and sex of the individual influences the expression of miR-146a in the frontal cortex.•The expression of IRAK1 and TRAF6 is not altered by long-term alcohol misuse.•Increased expression of miR-146a correlates with altered target gene expression in controls, but not in individuals with alcohol use disorder.•Long-term alcohol misuse may result in a loss of regulatory control of the TLR4 pathway by miR-146a. Long-term alcohol misuse triggers cellular adaptions in susceptible regions of the human brain, resulting in neurodegeneration, neuroinflammation and altered gene expression. Previous studies have identified ∼35 miRNAs, including miR-146a-5p, which are up-regulated in the frontal cortex of males with alcohol use disorder (AUD), but the influence of liver cirrhosis and sex is unknown. The expression of miR-146a-5p, IRAK1, and TRAF6 was measured in the prefrontal cortex of controls and individuals with AUD with and without cirrhosis of the liver. Further, individuals were genotyped for two SNPs, rs2910164 and rs57095329. The expression of miR-146a-5p was significantly different between sexes. In males the expression of miR-146a-5p was increased in individuals with AUD with and without liver cirrhosis compared with controls. In females miR-146a-5p expression was significantly lower in individuals with AUD compared with both controls and those with AUD and cirrhosis, suggesting that both the severity of alcohol misuse and the sex of the individual influences the expression of miR-146a-5p. The expression of TRAF6 was significantly lower in individuals with uncomplicated AUD compared with those with AUD and cirrhosis. The expression of IRAK1 did not differ between groups or sexes. There was no influence of genotype on expression. Increased expression of miR-146a-5p did not correlate with decreased IRAK1 or TRAF6 expression suggesting a loss of regulatory control of the TLR4 pathway. Understanding sex-specific differences in the regulation of gene expression in AUD is key to determine which inflammatory pathways could be targeted for therapeutic intervention.