The progression of NAFLD is influenced by suppression of two immune-related GTPases

Background/Aim:

The cause of non-alcoholic fatty liver disease (NAFLD) is multifactorial including genetic and environmental factors. In a backcross population of New Zealand obese (NZO) and C57BL/6J (B6) mice, a major quantitative trait locus (QTL), Ltg/NZO on chromosome 18, for increased liver triglycerides was identified. The aim of the study is to characterize the role and function of two causal gene variants of Ltg/NZO in vivo.

Methods:

Recombinant congenic mice carrying 5.3 Mbp of Ltg/NZO were fed a high-fat diet and metabolically characterized concerning their hepatic insulin sensitivity and lipid profile. Bioinformatics analysis and Electrophoretic Mobility Shift Assay (EMSA) were performed to elucidate the genetic cause for the differential expression pattern.

Results:

NZO-allele carriers (Ltg/NZO ^N/N) showed 2-fold higher liver triglyceride concentration than B6-allele carriers (Ltg/NZO ^N/B). Furthermore, Ltg/NZO ^N/N revealed impaired hepatic insulin sensitivity in line with higher diacylglycerol levels. Haplotype mapping and expression studies identified two immune-related GTPases as most likely candidates of Ltg/NZO which were 5 – 20-fold lower expressed in livers of Ltg/NZO ^N/N compared to Ltg/NZO ^N/B mice. An upstream active enhancer element harboring a FOXO1-binding motif was identified carrying a single nucleotide deletion in Ltg/NZO ^N/N alleles. This alteration could be explained by an impaired FOXO1 binding. Moreover, the human orthologue IRGM is significantly lower expressed in the liver of NAFLD patients compared to that of lean subjects.

Conclusion:

A sufficient expression of IRGM and its orthologous prevent the hepatic accumulation of triglycerides in humans and mice.