P2990
Over-expressing hematopoietic ABCA1 and ABCG1 re-configures the plasma membrane against inflammation, insulin resistance and atherosclerosis in diet-induced obesity

Extract

Introduction: Dietary fat promotes pathological insulin resistance through chronic macrophage inflammation. Membrane lipids affect the innate immune response, which requires domains that affect diet-induced chronic inflammation and change cell function based on phospholipids. ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) affect membrane compositions synergistically. However it is unknown if over-expressing hematopoietic ABCA1 and ABCG1 would re-configure the plasma membrane, therefore protect against inflammation, insulin resistance and atherosclerosis.

Purpose: Determine the effects and mechanisms of over-expressing hematopoietic ABCA1 and ABCG1 on plasma membrane microdomain compositions, insulin resistance and atherosclerosis in diet-induced obesity.

Methods: Hematopoietic ABCA1 and ABCG1 over-expressing LDLR−/− mice were fed the high fat, high sucrose with 0.15% cholesterol diabetogenic diet for up to 22 weeks. Whole body insulin resistance were evaluated by IPGTT and IPITT and atherosclerotic lesions were determined using a Movat's pentachrome stain. Detergent-resistance microdomain protein compositions were determined using proteomics.

Results: We found that over-expressing hematopoietic ABCA1 and ABCG1 significantly alleviated diet-induced insulin resistance and reduced atherosclerosis. The improved insulin resistance and reduced atherosclerosis in hematopoietic ABCA1 and ABCG1 over-expressing mice were accompanied with deceased monocytosis, reduced macrophage accumulation and inflammation in adipose tissue atherosclerotic lesions. Over-expressing hematopoietic ABCA1 and ABCG1 altered membrane order and microdomain protein compositions, impairing the retention of plasma membrane cholesterol and disrupting signaling pathways that are required for cell proliferation and inflammation.