Foxa2 activity increases plasma high density lipoprotein levels by regulating apolipoprotein M

Area of Science:

• Metabolic disease research
• Lipid metabolism and atherosclerosis
• Molecular endocrinology

Background:

• Obesity, diabetes, and insulin resistance are linked to dyslipidemia, including low high-density lipoprotein (HDL) and high triglycerides, increasing atherosclerosis risk.
• The precise molecular pathways connecting insulin resistance to reduced HDL levels remain largely unclear.
• Apolipoprotein M (apoM) is a key factor influencing plasma HDL concentrations and particle composition.

Purpose of the Study:

• To elucidate the molecular mechanism by which insulin, in states of insulin resistance, affects HDL metabolism.
• To investigate the role of the transcription factor Foxa2 in regulating apolipoprotein M (apoM) expression and its impact on HDL levels.
• To explore potential therapeutic targets for managing dyslipidemia and preventing atherosclerosis.

Main Methods:

• Utilized obese mouse models with induced hyperinsulinemia to study gene expression and lipid profiles.
• Employed viral vectors for nuclear reexpression of Foxa2, including a phosphorylation-deficient mutant (Foxa2T156A), in mouse models.
• Generated and analyzed haploinsufficient Foxa2(+/-) and apolipoprotein M knockout (apoM(-/-)) mice to determine causal relationships.

Main Results:

• Insulin was found to inhibit apolipoprotein M (apoM) expression through a Foxa2-dependent mechanism.
• Obese, hyperinsulinemic mice exhibited reduced apoM expression and lower pre-beta-HDL levels due to Foxa2 inactivation.
• Restoring Foxa2 function increased apoM expression and plasma pre-beta-HDL and HDL levels, an effect dependent on apoM.
• Foxa2's regulation of HDL levels and pre-beta-HDL formation is exclusively mediated by apoM.

Conclusions:

• Identified a novel mechanism where insulin suppresses apoM expression via Foxa2, contributing to low HDL levels in insulin resistance.
• Demonstrated that Foxa2 is a critical regulator of hepatic apoM expression and subsequent HDL metabolism.
• Findings suggest that modulating the insulin-Foxa2-apoM pathway could offer a therapeutic strategy for atherosclerosis prevention.