Title: Lipoprotein Lipase in the Arterial Wall
Description: Arterial LDL deposition is a key step in initiating atherosclerosis. Saturated fat (SAT)-enriched diets increase arterial LDL deposition, total and selective LDL-cholesterol uptakes, and arterial lipoprotein lipase (LpL). Because consumption of n-3 fatty acids (FA), such as EPA and DHA, potentially reduces the risk for cardiovascular disease (CVD), we investigated the mechanisms whereby dietary FA, metabolic syndrome and LpL interact to influence arterial lipid uptake in atherosclerosis. We hypothesized that specific FA, SAT versus n-3, alter the recruitment of different cell populations to the arterial wall and modulate arterial LpL levels and distribution, which in turn affects the development of atherosclerosis. To test these hypotheses, we carried out a series of dietary feeding studies in different mouse models to determine the effects of saturated versus n-3 FA on LDL-cholesterol delivery and arterial LpL levels. The data presented in this thesis demonstrate that high levels of saturated FA and insulin resistance contribute to accumulation of macrophages that secrete LpL and thus favor the development of atherosclerosis.

Furthermore, deficiency of LpL in the arterial wall reduced aortic macrophage populations and macrophage infiltration. The reconstitution of macrophage expressing LpL in LpL knockout models led to increases in macrophage populations in the arterial wall. Macrophage-associated LpL may increase "anchoring" of LDL and macrophages. n-3 FA decrease the presence of inflammatory macrophages and LpL; hence are associated with less arterial cholesterol delivery, inflammation and atherosclerosis. In an atherosclerosis-prone mouse model (LDLR-/-), gradual replacements of SAT with n-3 ameliorates abnormal lipid profiles and atherosclerosis. Thus, n-3 FA decrease risk for CVD in part by decreasing arterial macrophage-associated LpL. Interacting factors, such as PPARβ/Î´, likely play an important role in regulation of arterial-wall LpL levels in response to FA. Increased arterial Foxo1 expression can contribute to decreased PPARÎ± levels in the group fed n-3 FA. The levels of GPIHBP1 in the arterial wall correlate with arterial macrophage number.

This indicates the existence of other pathways important in mediating changes in LpL levels and arterial lipid deposition. These studies as described here defined 'novel' mechanisms underlying the potential of n-3 FA to decrease risk for CVD.