Obesity alters the partitioning of glycerol metabolism pathways in NAFLD

Results: miR-144 upregulation in obesity was associated with reduced expression of Irg1, which was restored upon miR-144 silencing in vitro and in vivo.Furthermore, miR-144 overexpression reduces Irg1 expression and the production of itaconate in vitro.In alignment with the reduction in IRG1 and itaconate levels, SDH activity was upregulated during obesity.Surprisingly, also fumarate hydratase (FH) activity was upregulated in obese livers, leading to fumarate depletion.miR-144 silencing selectively reduced the activities of both SDH and FH resulting in the accumulation of their related substrates succinate and fumarate.Moreover, molecular dynamics analyses revealed the potential role of itaconate as a competitive inhibitor of not only SDH but also FH.Combined, these results demonstrate that miR-144 inhibits the activity of NRF2 through decreased fumarate production in obesity.Conclusion: miR-144 triggers hyperactivation of FH in the TCA cycle and consumption of its substrate fumarate, eventually inhibiting NRF2 activity.Therefore, herein we unraveled miR-144 immunometabolic role in obesity in the regulation of endogenous antioxidant response.