Hepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During Obesity

Area of Science:

• Metabolic disease research
• Molecular biology
• Oxidative stress mechanisms

Background:

• Obesity-associated metabolic complications, including nonalcoholic fatty liver disease, are linked to oxidative stress.
• Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the antioxidant response.
• MicroRNA 144 (miR-144) has been identified as a regulator of NRF2 protein levels and activity.

Purpose of the Study:

• To investigate the mechanism by which hepatic miR-144 inhibits NRF2 activity in obesity.
• To explore the role of the tricarboxylic acid (TCA) metabolite fumarate in miR-144-mediated NRF2 regulation.
• To elucidate the impact of miR-144 on TCA cycle enzymes and antioxidant response in obesity.

Main Methods:

• Transcriptomic analysis of liver macrophages (LMs) in obese mice to identify miR-144 targets.
• Analysis of immuno-responsive gene 1 (Irg1) expression and its product itaconate.
• Assessing TCA enzyme activities (SDH, FH) and kinetics in obese mice and human liver organoids after miR-144 manipulation.
• Utilizing single-cell activity assays and molecular dynamic simulations.

Main Results:

• Obesity elevates miR-144, reducing Irg1 expression and itaconate production, which normally inhibits succinate dehydrogenase (SDH).
• Despite reduced itaconate, SDH activity is upregulated in obesity.
• Fumarate hydratase (FH) activity is paradoxically upregulated, consuming fumarate; miR-144 silencing normalizes SDH and FH activities, restoring fumarate and succinate levels.
• Itaconate may also inhibit FH, with miR-144 silencing impacting both enzymes.

Conclusions:

• Hepatic miR-144 inhibits NRF2 activity in obesity by activating FH, leading to fumarate depletion.
• This activation of FH by miR-144 impairs the TCA cycle and the cellular antioxidant response.
• Targeting miR-144 may offer a therapeutic strategy for obesity-related liver disease and metabolic dysfunction.