How Is Lipoprotein Disposition Influenced By Fenestrae In The Hepatic Sinusoidal Endothelium?
Funder
National Health and Medical Research Council
Funding Amount
$310,500.00
Summary
Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully d ....Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully define the role of fenestrae in the ultrafiltration of particles such as lipoproteins and microspheres. This will confirm that ultrafiltration by fenestrae in the liver endothelium is an important biological process akin to filtration by the kidney, and relevant for lipoprotein metabolism. We will determine whether oxidative stress, which generates large gaps in the sinusoidal endothelium, increases the transfer of lipoproteins into the liver. This provides a novel mechanism for fatty liver that follows toxic liver injury, and hence, a therapeutic target for this condition. We will determine whether loss of fenestrae induced by the synthetic non-ionic surfactant, pluronic 407, reduces transfer of lipoproteins. This is an entirely novel mechanism and risk factor for hyperlipidaemia. Finally we will investigate lipoprotein (a) which is a potent risk factor for vascular disease. We will assess with lipoprotein (a), through binding other lipoproteins and increasing their size, impedes their transfer through the fenestrations for subsequent hepatic metabolism. From the basic perspective, these studies will prove that fenestrations in the liver endothelial cell are an ultrafiltration system that is significant for lipoprotein metabolism. From the clinical perspective, the studies will generate novel mechanisms for impaired hepatic metabolism of lipoproteins as well as indicating that fenestrae are a potential target for the development of lipid-lowering pharmacotherapies.Read moreRead less
An Intervention To Improve The Detection And Management Of Familial Hypercholesterolaemia In Primary Care
Funder
National Health and Medical Research Council
Funding Amount
$518,588.00
Summary
Familial hypercholesterolaemia (FH) is an inherited condition affecting 45,000 Australians, with 10% diagnosed. FH has been managed mainly through hospital clinics with the majority under-treated despite effective primary care treatment being available. The application integrates specialist and primary care management with data fed into the new national FH registry. It is a partnership between 7 Universities and 5 States: service providers; community organisations; policy managers and industry.
The Vasoprotective Actions Of Flavonoids In Ischaemia And Hypercholesterolaemia
Funder
National Health and Medical Research Council
Funding Amount
$181,018.00
Summary
Diet has a major influence on the incidence of coronary artery disease. Thus in populations where large amounts of fruits, vegetables and legumes are consumed with a low proportion of food from animal sources there is a relatively lower incidence of coronary artery disease. A possible explanation for the beneficial actions of this diet is that it provides a high level of compounds called flavonoids. Flavonoids have a number of biological actions that may prevent coronary artery disease. Flavonoi ....Diet has a major influence on the incidence of coronary artery disease. Thus in populations where large amounts of fruits, vegetables and legumes are consumed with a low proportion of food from animal sources there is a relatively lower incidence of coronary artery disease. A possible explanation for the beneficial actions of this diet is that it provides a high level of compounds called flavonoids. Flavonoids have a number of biological actions that may prevent coronary artery disease. Flavonoids can relax blood vessels which would improve blood flow to organs. In addition they may lower the level of LDL cholesterol, the bad form of cholesterol that promotes artery narrowing. They may also have actions that prevent damage that normally occurs to organs when there is an interruption to blood flow, such as occurs when someone has a heart attack or stroke. This project will investigate the ability of selected flavonoids to prevent injury to blood vessels that occurs when there is an interruption to blood flow or when cholesterol levels are too high. Understanding the actions of flavonoids may lead to the development of new therapies to prevent or treat heart attacks and stroke.Read moreRead less
Vascular Effects Of Exercise Training And Lipid-lowering Therapy At Rest And During Exercise In Hypercholesterolaemia
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
The health of the cells which line blood vessels, endothelial cells, is now known to be important in maintaining normal function of the circulation. In patients with elevated blood cholesterol concentration, the function of these cells is abnormal and this is considered to contribute importantly to the blood vessel dysfunction and cardiovascular disease seen in this condition. We have recently demonstrated that drug therapy aimed at decreasing cholesterol concentration in the blood can significa ....The health of the cells which line blood vessels, endothelial cells, is now known to be important in maintaining normal function of the circulation. In patients with elevated blood cholesterol concentration, the function of these cells is abnormal and this is considered to contribute importantly to the blood vessel dysfunction and cardiovascular disease seen in this condition. We have recently demonstrated that drug therapy aimed at decreasing cholesterol concentration in the blood can significantly improve blood vessel function. In other studies we have demonstrated that exercise training improves blood vessel function. The purpose of this research is to determine whether high blood cholesterol impairs exercise capacity by limiting blood flow to exercising muscle. It is also our goal to determine whether exercise training can produce benefit additional to that resulting from lowering cholesterol in those with initially high cholesterol. Blood vessel function will be studied at rest, in response to pharmacological stimulation and during exercise. Vascular function in the forearm will be assessed using synchronised ultrasound (high frequency sound, sonar) and Doppler measures which assess the size of, and flow in, the large artery near the elbow crease. During measurements, procedures are undertaken to alter flow in the arm blood vessels, some depending upon functional ability of the endothelial cells and some independent of those cells. In addition to assessment of blood vessel function, measurements of exercise tolerance will be taken before and after each intervention. By examining the effects of lipid-lowering and exercise training on rest and exercise blood flow responses, this research will help determine the best approach to improving blood vessel function and cardiovascular fitness in patients with high cholesterol.Read moreRead less
Lipid Metabolism In The Aromatase Knock-out Mouse (ArKO)
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermi ....Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermineralisation of the bones, intra-abdominal obesity, hypercholesterolaemia and insulin resistance. We are addressing the mechanisms of all of those phenotypes but in the present application we focus on the abnormalities in lipid metabolism. Thus we will seek to understand the increase in adiposity by examining the role of oestrogen in lipid synthesis, oxidation and breakdown in adipose tissue from intra-abdominal sites. We will also examine the role that oestrogen plays in cholesterol uptake, synthesis and catabolism by the liver as well as fatty acid synthesis and oxidation by the liver. These studies will be correlated with whole body parameters such as feeding behaviour, physical activity, energy expenditure, glucose and fat oxidation rates. We will also examine the effect of feeding a high cholesterol or a high fat diet on lipid metabolism in the oestrogen deficient animals, and we will determine the effect of oestradiol and isoflavone replacement on the phenotype. In this way we aim to reach a better understanding of the multiplicity of roles that oestrogens play in the regulation of lipid and cholesterol metabolism in both males and females. The results of such studies will be the development of better strategies to deal with pathologies resulting from disturbances in cholesterol and lipid metabolism.Read moreRead less