The Role of Apolipoprotein A-V in Chylomicron Metabolism Cardiovascular disease, diabetes and obesity are major clinical problems worldwide, and elevated plasma triglyceride (TG) levels constitute an independent risk factor for these chronic disorders. Discovered in 2001, apolipoprotein A-V (apoA-V) is a protein synthesized and secreted by the liver and its levels are inversely proportional to plasma TG levels. Compared with other apolipoproteins, such as apoA-IV and apoA-I, apoA-V circulates at extremely low concentrations, raising the question as to how such a low circulating apolipoprotein can exert such a profound effect on plasma TG. While apolipoproteins serve many roles in lipid metabolism, the mechanism behind apoA-V's ability to lower plasma TG levels is not clear. Our lab was the first to report that apoA-V regulates the production and secretion of chylomicrons (CMs) by the small intestines. We found that: 1) apoA-V knockout (KO) mice are significantly better in the absorption and lymphatic transport of both TG and cholesterol than WT animals; 2) apoA-V KO mice secrete more apoB48 (therefore have more CM particles since there is one apoB48 per particle) into lymph than WT animals; 3) apoA-V is secreted into lymph during active fat absorption associated with CMs; and 4) apoA-V is present in bile, representing a second route of apoA-V transport, with the first being the circulation. In this proposal, we will investigate 1) the importance of apoA- V transport to the small intestine via bile; and 2) the importance of apoA-V on CM metabolism following its secretion from the intestine. First, we will determine whether the formation and secretion of CMs by the small intestines is influenced by apoA-V from the circulation versus that from the bile. Second, we will determine if and how apoA-V regulates the metabolism of CMs. Precisely, we will determine the importance of apoA-V in CMs versus apoA-V in the circulation in the metabolism of CMs. Information from the proposed studies may provide insight to our understanding of the inverse relationship between circulating apoA-V and plasma TG levels. The proposed research is not only novel, but it also takes advantage of the unique conscious lymph fistula mouse model. Training in carrying out lymph fistula mouse and various biochemical and physiological studies will be invaluable in establishing me as a biomedical researcher in lipoprotein (especially CM) and lipid metabolism. The proposed studies may also provide insight into the therapeutic treatment of hypertriglyceridemia, obesity, diabetes and cardiovascular disease. Hypothesis: ApoA-V is secreted by the liver into the bile to regulate CM formation and secretion by the gut so as not to overwhelm the metabolic capacity of the liver; e.g. following hepatectomy.
AIM 1 : Since the liver is the only organ that synthesizes and secretes apoA-V, we will determine whether the formation and secretion of CM by the gut is influenced by apoA-V from bile versus from circulation.
AIM 2 : To determine if and how apoA-V regulates the metabolism of CMs.
Understanding the mechanism of how apoA-V lowers plasma triglycerides may contribute significant insight in the therapeutic treatment of hypertriglyceridemia, diabetes, and cardiovascular diseases. Since the liver is the only known organ to synthesize and secrete apoA-V, in the proposed studies, we will investigate the importance of apoA-V transport to the small intestines via bile or circulation in the absorption and lymphatic transport of triglyceride. Additionally, we will determine the importance of apoA-V on the chylomicron particles versus the apoA-V in the circulation, in the metabolism of chylomicrons.
