Lipoprotein Oxidation, Antioxidants And Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$281,812.00
Summary
We are studying how major blood vessels harden. This process (called atherosclerosis) is the major underlying cause of heart disease, the major single cause of death of Australians. Our research focusses on the 'Oxidation Theory', one of the most common theories of how atherosclerosis develops. Accordingly, fats in fat-carrying particles (called lipoproteins) penetrate the walls of blood vessels, where they cause disease as a result of going rancid. This is a primary reason for the general publi ....We are studying how major blood vessels harden. This process (called atherosclerosis) is the major underlying cause of heart disease, the major single cause of death of Australians. Our research focusses on the 'Oxidation Theory', one of the most common theories of how atherosclerosis develops. Accordingly, fats in fat-carrying particles (called lipoproteins) penetrate the walls of blood vessels, where they cause disease as a result of going rancid. This is a primary reason for the general public's interest in antioxidant supplements to combat heart disease. However, it is not clear at present whether rancid fats is a cause or consequence of atherosclerosis, and we recently showed that the two processes can be dissociated in an animal model of the disease. This application addresses the question of whether the process of fats going rancid can be generally dissociated from atherosclerosis, using several different animal models of the disease. We will distinguish different chemical pathways that give rise to different types of rancid fats, and between rancid fats and 'rancid' proteins. Such studies have not been carried out to date. Our underlying hypothesis is that the process of lipoprotein fat going rancid is a consequnece rather than a cause of atherosclerosis and heart disease. By testing this hypothesis, we will provide a rationale for whether antioxidant supplements aimed at preventing rancid fats from accumulating are likely of benefit in terms of preventing heart disease. This is of direct interest to public health. Our studies also address the issue of how antioxidants (if not through preventing fats from going rancid) attenuate atherosclerosis. We will focus on a particular synthetic antioxidant for which there is strong evidence that it is beneficial in preventing the re-narrowing of blood vessels in humans undergoing coronary angioplasty. These studies have the potential to provide new clues for the development of novel drugs against heart disease.Read moreRead less
Factors Controlling Lipid Accumulation In Non-adipose Tissues
Funder
National Health and Medical Research Council
Funding Amount
$463,500.00
Summary
The fat cells of the body are designed to store excess fuel for use when supply from the diet is low, or in situations like exercise, demand is high. Fat also accumulates to some extent in the cells of other tissues types, but in some people the accumulation is excessive. This can have a number of serious effects. In the liver and muscle it can interfere with the ability of insulin to properly regulate the amount of glucose present in the blood, contributing to the development of diabetes. In th ....The fat cells of the body are designed to store excess fuel for use when supply from the diet is low, or in situations like exercise, demand is high. Fat also accumulates to some extent in the cells of other tissues types, but in some people the accumulation is excessive. This can have a number of serious effects. In the liver and muscle it can interfere with the ability of insulin to properly regulate the amount of glucose present in the blood, contributing to the development of diabetes. In the liver, fat accumulation can also lead to cirrhosis and liver failure. Cardiovascular complications, resulting in premature death, are also likely. However despite these devastating consequences it is not clear what the underlying cause of the over-accumulation of fat is not known. In this project we will investigate in detail several aspects of fat metabolism that we think are important in controlling how tissues take up fat from the circulation and whether it is subsequently stored or burnt for energy. We will study the amount of fat that is taken up by different tissues of the body under a range of conditions including fed, and short- and long-term fasting. We will also use drugs to inhibit or promote the amount of fat that is burnt, to see if this changes the rate at which fat is taken up by different tissues. In addition we will accelerate, by genetic manipulation, the rate at which some key enzymes of fat metabolism are produced, to determine their effect on the amount of fat that is stored by different tissue types. Our aim is to determine the metabolic processes that influence fat accumulation in those adversely affected tissues such as liver, heart and skeletal muscle. The identification of the most important processes will contribute significantly to the targeting of therapies aimed at preventing excess fat accumulation and its associated diseases.Read moreRead less
The Role Of Seipin In Lipid Metabolism And Adipogenesis
Funder
National Health and Medical Research Council
Funding Amount
$397,749.00
Summary
The prevalence of obesity and its related disorders has reached an alarming level in Australia and other developed countries. Obesity is characterized by accumulation of fully-differentiated adipocytes loaded with lipid droplets (LDs). Therefore, understanding the cellular dynamics of LDs and the molecular mechanisms of adipogenesis (adipocyte differentiation) is of crucial importance in our battle against obesity. Our proposed study will help undertand the mechnisams of obesity.
Lipoprotein Metabolism And Mutations Of The APOB Gene Causing Familial Hypobetalipoproteinaemia
Funder
National Health and Medical Research Council
Funding Amount
$396,179.00
Summary
Cardiovascular disease is an increasing problem in Australia, however, the cause of atherosclerosis is incompletely understood. A protein, known as apolipoprotein (apo) B, plays a central role in lipoprotein metabolism. Elevated levels of apoB are characteristic of many forms of hypercholestrolaemia. Familial combined hyperlipidaemia and polygenic hypercholesterolaemia are two common inherited disorders of lipoprotein metabolism that are characterised by elevated apoB levels in the blood and ear ....Cardiovascular disease is an increasing problem in Australia, however, the cause of atherosclerosis is incompletely understood. A protein, known as apolipoprotein (apo) B, plays a central role in lipoprotein metabolism. Elevated levels of apoB are characteristic of many forms of hypercholestrolaemia. Familial combined hyperlipidaemia and polygenic hypercholesterolaemia are two common inherited disorders of lipoprotein metabolism that are characterised by elevated apoB levels in the blood and early atherosclerosis. In contrast, familial hypobetalipoproteinemia is a rare inherited disorder of lipoprotein metabolism characterised by very low levels of cholesterol and apoB in the blood and resistance to atherosclerosis and cardiovascular disease. The focus of this research project is to explore the regulation of apoB metabolism using individuals from unique families with familial hypobetalipoproteinaemia. First, we will determine and characterise the alterations in the APOB gene causing the low cholesterol levels in families with familial hypobetalipoproteinaemia. Second, we will determine if these apoB alterations affect the production and-or clearance of blood fats, or lipoproteins in affected individuals, when compared to controls, by performing metabolic studies. The proposed human in vivo metabolic studies will lead to a better understanding of the mechanism(s) involved in the assembly, secretion, transport, and clearance of plasma apoB-containing lipoproteins. Furthermore, these studies may reveal new protective mechanisms and potentially aid in the development of strategies to suppress over-production of apoB-containing lipoproteins in reciprocal conditions such as familial combined hyperlipidaemia or polygenic hypercholesterolaemia.Read moreRead less