Ifgga2: A novel repressor of a fatty liver

Background/Aim:

The prevalence of fatty liver progression increases worldwide, caused by environmental and genetic factors whereas the last still remains incompletely defined. A new locus on chromosome 18, Ltg/NZO, associated with increased liver triglycerides was identified in a backcross population of New Zealand obese (NZO) and C57BL/6J (B6) mice. The hypothesis was that a reduced expression of an immune-related GTPase Ifgga2, which is the most likely responsible gene in the Ltg/NZO locus, associates with elevated hepatic fat content.

Methods:

Recombinant congenic mice carrying 5.3 Mbp of Ltg/NZO on a NZO-background were fed a high-fat diet (45 kcal% from fat) and analyzed to their liver fat content. A designed miRNA targeting Ifgga2 was injected into B6-mice and hepatic fat accumulation was measured.

Results:

Mice carrying NZO-alleles for the critical region of Ltg/NZO (Ltg/NZO.5.3N/N) showed 4-fold higher liver triglyceride concentrations in comparison to homozygous B6-allele carriers (Ltg/NZO.5.3B/B). Haplotype mapping and expression studies identified two immune-related GTPases, Ifgga2 and Ifgga4, as most likely candidates, both lower expressed in livers of Ltg/NZO.5.3N/N compared to Ltg/NZO.5.3B/B mice by 12- and 30-fold. Due to the nearly exclusive hepatic expression of Ifgga2, liver-specific downregulation was achieved by applying a designed miRNA. These mice exhibit a 3.5-fold increased hepatic fat accumulation compared to control mice. Moreover, the human orthologue IRGM was significantly lower expressed in livers of NAFLD patients compared to lean individuals.

Conclusion:

In conclusion, our data indicate that Ifgga2 and its human orthologue IRGM are repressors of hepatic steatosis.