Caloric Restriction, Ageing And The Liver Sinusoidal Endothelium: Mechanisms And Implications
Funder
National Health and Medical Research Council
Funding Amount
$366,216.00
Summary
Old age is the major risk factor for many diseases yet the mechanism is unknown. We discovered age-related changes in the liver sinusoidal endothelial cell that provide a mechanism for the link between old age, lipid metabolism and vascular disease. The liver sinusoidal endothelial cell influences the transfer of substrates between the blood and liver cells, therefore changes in the liver sinusoidal endothelial cell affect liver function. We discovered major structural changes in the liver sinus ....Old age is the major risk factor for many diseases yet the mechanism is unknown. We discovered age-related changes in the liver sinusoidal endothelial cell that provide a mechanism for the link between old age, lipid metabolism and vascular disease. The liver sinusoidal endothelial cell influences the transfer of substrates between the blood and liver cells, therefore changes in the liver sinusoidal endothelial cell affect liver function. We discovered major structural changes in the liver sinusoidal endothelial cell in old age called pseudocapillarization, consisting of loss of pores, increased thickness and deposition of collagen and basal lamina. We showed that the loss of pores prevented the uptake by the liver of some lipoproteins, with implications for age-related changes in lipid metabolism and vascular disease. We have now found that caloric restriction delays pseudocapillarization. Caloric restriction is the only intervention known to increase maximal life span. This effect of caloric restriction is mediated by a protein called SIRT1 through actions on mitochondria and cell death. A naturally occurring agonist of SIRT1 called resveratrol has been found to increase longevity in yeast, worms and flies. We hypothesize that caloric restriction prevents age-related cardiovascular disease by delaying pseudocapillarization and hence maintaining hepatic metabolism of lipoproteins, particularly chylomicron remnants. We propose that caloric restriction will prevent age-related pseudocapillarization via its effects on the SIRT1 pathways and therefore pseudocapillarization will be delayed by resveratrol. Confirmation of these hypotheses will generate a unique target - pores in the liver sinusoidal endothelial cell - for the prevention of vascular disease in older people and provide a platform for the development of novel pharmacological agents such as resveratrol that act by maintaining the porosity of the liver sinusoidal endothelial cell.Read moreRead less
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
Does Immunosuppression Affect The Post-transplantation Hepatic Fibrogenic Response?
Funder
National Health and Medical Research Council
Funding Amount
$360,000.00
Summary
Liver transplantation is often the only treatment option for patients who progress to end-stage liver disease after initial treatment has failed. Unfortunately, re-emergence of disease is common and patients often develop fibrosis and cirrhosis (scarring of the liver) in the donor organ. In some cases it has been observed that this scarring often develops rapidly, sometimes in a year or less following transplantation. Re-transplantation is often required. This differs from the usual progression ....Liver transplantation is often the only treatment option for patients who progress to end-stage liver disease after initial treatment has failed. Unfortunately, re-emergence of disease is common and patients often develop fibrosis and cirrhosis (scarring of the liver) in the donor organ. In some cases it has been observed that this scarring often develops rapidly, sometimes in a year or less following transplantation. Re-transplantation is often required. This differs from the usual progression of cirrhosis pre-transplant which often takes years or decades to develop. While essential to prevent rejection of the transplanted organ, immunosuppression is not without side effects. To date, few studies have examined the effect of immunosuppressive agents on the development of hepatic fibrosis and the key fibrosis effector cell type, the hepatic stellate cell. These reports have shown that one of the most commonly used immunosuppressant agents (FK-506) may adversely influence fibrosis progression while rapamycin may prevent fibrosis progression. However little is known regarding the mechanisms through which this occurs. We propose to examine the effect of four different immunosuppressants on fibrosis development both in vitro and in vivo to determine whether scar development or scar breakdown pathways are altered post-immunosuppression. If the factors driving the fibrogenesis in the transplanted organ can be elucidated it may then be possible to develop therapeutic strategies to tackle the problem. This may result in a reduced need for re-transplantation which has obvious benefits to the transplant patient but would also reduce the numbers of donor organs required.Read moreRead less
Role For Sphingosine Kinase-1 In Endothelial Progenitor Cell Survival And Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$294,205.00
Summary
Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand th ....Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand the process whereby mature endothelial cells are formed and how replacement of damaged endothelial cells is normally achieved. Stem cell therapy is considered the new frontier for the treatment of many diseases. Understanding how endothelial progenitor cells differentiate to mature endothelial cells and the signals which operate inside the cell may allow therapeutic manipulation of key target moecules in order to limit or control inflammation, tumourigenesis, rheumatoid arthritis and diabetic retinopathy. Our results suggest that one target maybe the enzyme sphingosine kinase.Read moreRead less
The lining of the uterus is unusual compared to other parts of the adult body in that new blood vessels grow and then breakdown during menstruation every month. The aim of this project is to understand what controls the growth and regression of these uterine blood vessels. This information is of immediate relevance to a number of clinical problems where an ability to either promote or prevent blood vessel growth would be of major advantage. For example, increased blood vessel growth would accele ....The lining of the uterus is unusual compared to other parts of the adult body in that new blood vessels grow and then breakdown during menstruation every month. The aim of this project is to understand what controls the growth and regression of these uterine blood vessels. This information is of immediate relevance to a number of clinical problems where an ability to either promote or prevent blood vessel growth would be of major advantage. For example, increased blood vessel growth would accelerate wound healing, while blocking blood vessel growth would prevent the growth and spread of cancers. Another disorder that could be controlled through preventing blood vessel growth is endometriosis, a disease where cells from the lining of the uterus grow inside the abdomen causing pain and infertility. Endometriosis affects upto 10% of women.Read moreRead less