The role of phospholipid transfer protein (PLTP) in lipoprotein metabolism and atherosclerosis.

Abstract

Plasma phospholipids transfer protein (PLTP) is a member of the lipid transfer/lipopolysaccharide binding protein gene family. PLTP is an independent risk factor for coronary artery disease. PLTP deficiency decreases and PLTP overexpression increases atherosclerosis in mouse models. Therefore, PLTP is considered as a potential target for pharmacological or gene therapy. However, this is hampered by the fact that the mechanism by which PLTP is atherogenic is not completely understood. PLTP is a multi-functional protein that is expressed in a variety of tissues. Some effects of PLTP are considered atherogenic, while others are thought to be anti-atherogenic. In order to unravel the mechanisms, we have utilized two approaches to study the impact of PLTP deficiency on lipid metabolism and atherosclerosis. First, we explored the role of PLTP deficiency in macrophages, in terms of lipids metabolism and atherosclerosis. It is known that formation of macrophage-derived foam cells (which highly express PLTP as well as apoE, a well-known anti-atherogneic apolipoprotein) is the critical step in the process of atherosclerosis. To study the relationship between PLTP and apoE in macrophages, we transplanted PLTP-deficient mouse bone marrow into apoE-deficient mice, creating a mouse model with PLTP deficiency, and apoE expression exclusively in the macrophages. We found that macrophage PLTP deficiency significantly decreased PLTP activity, compared with controls. Moreover, macrophage-produced plasma apoE was significantly decreased in apoE-deficient recipients that received PLTP-deficient bone marrow relative to apoE-deficient recipients that received PLTP expressing bone marrow. On a western type diet, macrophage PLTP deficiency increased plasma cholesterol and phospholipid, mainly on non-HDL particles, thus increasing atherosclerotic lesions in the aortic arch and root, as well as the entire aorta. These results provided novel information concerning the effect of PLTP on apoE secretion in macrophages and its atherogenic consequences. Second, we investigated the role of PLTP deficiency in cholesterol absorption in small intestine, a process closely related to plasma cholesterol levels and atherosclerosis. We show that the absorption of a bolus of radiolabeled cholesterol (short-term) but not triglyceride in PLTP KO mice was significantly lower than that of wild type (WT) mice. Also, cholesterol transport to the plasma, small intestine, and liver was significantly lower in PLTP KO mice than that of WT ones. Long-term studies involving multiple feedings of radiolabeled lipids also showed significant reduction of cholesterol but not triglyceride absorption and transport to the plasma, small intestine, and liver in PLTP KO mice, compared to WT ones. Moreover, we found that, compared to WT mice, PLTP KO primary enterocytes secrete and absorb significant less cholesterol, Thus, PLTP KO mouse small intestine secretes less and accumulates more cholesterol, which, in turn, inhibit cholesterol absorption and this may provide a new mechanism for the reduction of atherosclerotic lesions in these mice.