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American Heart Association

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Final ID: 4141400

Inhibition of Chylomicron Uptake Stimulates Treg Accumulation

Abstract Body (Do not enter title and authors here): Introduction: Chylomicrons are major lipid fuel for cells. They contain dietary triglycerides, cholesterols, and apolipoproteins. In the intestine, apolipoprotein C-III (apoC-III) is produced during fat feeding, and secreted onto chylomicrons. ApoC-III is a key regulator of chylomicron hydrolysis and clearance through its inhibitory effects on lipoprotein lipase (LPL) and low-density lipoprotein receptor (LDLr) in multiple tissues. In humans, genetic polymorphisms in apoC-III are directly tied to plasma triglyceride levels and cardiovascular disease risk. As a result, apoC-III is a major drug target with antisense therapies already in clinical trials. Though plasma chylomicrons and the lipids they carry are well-known instigators of cardiovascular disease, they also deliver necessary lipid fuels to organs and cells that require energy. As an important regression factor in cardiovascular diseases, regulatory CD4+ Foxp3+T cells (Tregs) are a highly oxidative lymphocyte subset, and Tregs heavily rely on fatty acids to fuel their differentiation, proliferation, and anti-inflammatory functions.

Hypothesis: Though Tregs rely on FA for ATP generation, few studies consider how Tregs encounter their lipid fuel and whether this process is regulated. We hypothesized that chylomicrons deliver triglyceride to Tregs, and that apoC-III would regulate this process through receptor inhibition.

Methods: We used purified chylomicrons and albumin-bound fatty acid, Seahorse metabolic flux analysis of Tregs, and in vivo functional assays of inflammatory bowel disease. Finally, we asked whether these processes may be at play during atherosclerosis, where both Tregs and chylomicron lipids are critical factors.

Results: Our studies reveal: CD4+Foxp3+Tregs endocytose chylomicrons lipids (both FFA and cholesterol); oxidative phosphorylation in Tregs is stimulated by lipids in apoC-III containing chylomicrons; these events can be targeted to change Treg accumulation and suppressive function in the gut and the aorta. We find that the inhibition of chylomicron uptake by Tregs also coincides with an increase in Treg accumulation at sites of inflammation, and a decrease in their expression of apoptotic markers.

Conclusions: These data suggest a link between chylomicron lipid metabolism and apoptosis in anti-inflammatory Tregs. Further research will be conducted to reveal the mechanism of Treg chylomicron uptake and how regulation of this pathway alters Treg metabolism and apoptosis.
  • Wei, Zihan  ( University of Pittsburgh , Pittsburgh , Pennsylvania , United States )
  • Author Disclosures:
    Zihan Wei: DO NOT have relevant financial relationships
Meeting Info:

Scientific Sessions 2024

2024

Chicago, Illinois

Session Info:

Crosstalk Between Lipids and Inflammation in Various Tissues

Monday, 11/18/2024 , 08:00AM - 09:15AM

Abstract Oral Session

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