Date of Completion

8-9-2019

Embargo Period

6-1-2029

Keywords

apolipoprotein C-III, low-density lipoprotein receptor, enterocyte, dietary fat absorption, fatty acid oxidation, cytosolic lipid droplet, chylomicron, enteroids, organoids

Major Advisor

Alison Kohan

Associate Advisor

Rebecca A. Haeusler

Associate Advisor

Ji-Young Lee

Associate Advisor

Christopher Blesso

Associate Advisor

Nathan Alder

Field of Study

Nutritional Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Chylomicron metabolism plays a critical role in determining plasma levels of triacylglycerols (TAG) and cholesterol, both of which are risk factors for cardiovascular disease. The rates of chylomicron secretion and remnant clearance are controlled by intracellular and extracellular factors including apolipoprotein CIII (apoC-III). We have previously shown that human apoC-III overexpression in mice (apoC-IIITg mice) decreases the rate of chylomicron secretion into lymph, as well as the TAG composition in chylomicrons. We investigate whether enterocyte lipoprotein uptake regulates enterocyte metabolism and dietary lipid absorption in order to better our understanding of how the pathophysiological conditions (like hyperlipidemia, diabetes, and inflammation) potentiate atherogenic chylomicron secretion. In these studies, we measured the canonical intracellular chylomicron regulatory pathways (including chylomicron synthesis enzymes, fatty acid trafficking across the apical membrane, and cytosolic lipid droplet metabolism). We conclude that enterocytes take up TAG-rich lipoproteins (TRLs) on the basolateral face, that excess apoC-III decreases TRL uptake, and that this regulates chylomicron secretion and enterocyte metabolism. We propose that this pathway of basolateral lipid substrate transport (BLST) plays a physiologically relevant role in the maintenance of dietary lipid absorption and chylomicron secretion, and that the loss of BLST (during pathophysiological apoC-III levels in plasma) could be atherogenic.

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Available for download on Friday, June 01, 2029

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