Role of Dietary Nutrients in Induction of Pseudocapillarization and the Functional Consequences for Hyperlipidemia

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ABSTRACT The central tenet of this proposal is that the modern diet is enhanced in dietary nutrients due to food preparation techniques and a shift in dietary nutrients that leads over many years leads to a process called pseudocapillarization. Pseudocapillarization is defined as an ultrastructural change of liver sinusoidal endothelial cells (LSECs) that is seen in aging experimental animals and also in humans starting as early as the 4th decade of life. Pseudocapillarized LSECs also demonstrate functional changes, specifically in their ability to endocytose certain substrates. Pseudocapillarization has been linked to changes in serum lipids that are partially responsive or unresponsive to statin therapy and therefore contribute to the so-called residual risk for atherosclerosis (i.e. not treatable with statins). The overall objectives of this application are to understand the mechanisms that link dietary enhancements to morphological and functional changes seen in LSECs in aging, to establish the impact of these changes on hyperlipidemia, and to determine whether therapeutic strategies to reverse the aged LSEC phenotype might be clinically beneficial. Specific aims: aim 1 will examine possible pathways that link dietary changes to signaling that downregulates the nitric oxide pathway in LSECs to determine the aberrant signaling that leads to pseudocapillarization. Aim 2 will use cutting-edge methodology to re-examine the mechanism of chylomicron remnant clearance; will examine approaches to either reverse pseudocapillarization in aged rats or exacerbate the change in LSECs and examine the effect on post-prandial lipid profiles, lipid clearance by LSECs, LSEC endocytosis and ultrastructure; and will examine the endocytotic machinery involved in lipid clearance in LSECs from young rats, old rats and old rats with reversal of pseudocapillarization.