Iron Metabolism And The Cirrhotic Liver:studies On Iron Absorption And Hepatic Iron Kinetics
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
Patients with liver disease awaiting liver transplantation often have excess iron in the liver that aggravates the existing liver disease. We have shown that patients with cholestatic liver disease, (due to poor bile excretion), do not have much iron in the liver compared to those patients with hepatocellular cirrhosis, (where the liver cells are damaged). Why this is so is unknown. Iron is normally absorbed from the diet by with the help of special molecules in the small intestine, carried in t ....Patients with liver disease awaiting liver transplantation often have excess iron in the liver that aggravates the existing liver disease. We have shown that patients with cholestatic liver disease, (due to poor bile excretion), do not have much iron in the liver compared to those patients with hepatocellular cirrhosis, (where the liver cells are damaged). Why this is so is unknown. Iron is normally absorbed from the diet by with the help of special molecules in the small intestine, carried in the blood to the liver where it is used by the cells. We would like to study how the proteins that transport iron in the intestine function and see if this is a different in disease. We would also like to examine exactly which molecules are important in depositing iron in the liver in patients with cirrhosis. We will work on animal models of liver disease as well as humans. We will treat animals so that they have liver disease that resembles human subjects with cirrhosis. These treatments include (1) feeding the animals carbon-tetrachloride, a toxin which damages the liver cells and therefore causes hepatocellular liver injury, and (2) tying the bile duct which stops the flow of bile and this results in cholestatic liver injury. It is known which proteins takes iron into the normal liver cells but no one knows which molecules transport the iron in liver disease. We think they may be different, because when the liver becomes diseased, scarring occurs this results in cirrhosis. Molecules that could easily enter liver cells may now be too big to pass through the openings. These studies are important since they will suggest new treatments to patients with liver disease who are awaiting a liver transplant and the treatment will probably differ depending on which type of liver disease the patient has.Read moreRead less
Role Of Nuclear Receptors In Hepatic Injury And Fibrogenesis
Funder
National Health and Medical Research Council
Funding Amount
$443,520.00
Summary
Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually le ....Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually leads to cirrhosis if the injurious process is sufficiently intense and sustained. Liver cirrhosis is the precursor to several undesirable complications of liver disease, most notably primary liver cancer (also called hepatoma), liver failure and severe bleeding from the gut. Therefore, it is not surprising that effective strategies to control liver injury and prevent cirrhosis have been called the holy grail of liver research. To date the only therapies for substantially improving the outcome of patients with chronic liver disease are those that halt or remove the cause of injury. Unfortunately, in many cases it is still not possible to remove or effectively treat the cause of injury. Because of this there is intense interest in therapies that might favourably alter the response of the liver to injury and especially in those that may retard or inhibit scarring and prevent cirrhosis. Nuclear receptors are sensors that control many aspects of the body's metabolism, especially the metabolism of cholesterol and fat. Recently, our work and that of others has suggested that some nuclear receptors may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so, and which of the several nuclear receptors likely to be involved are the important ones. We will then extend these studies to see if drugs that activate these receptors will improve or prevent severe liver disease.Read moreRead less
Steroidogenic Factor-1, A Novel Regulator Of Hepatic Stellate Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$589,458.00
Summary
Recently, we have discovered that steroidogenic factor-1, a specialized protein that directs cells to make steroid hormones, is present in cells in the liver called stellate cells. This may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so and how this system functions. This work will provide a basis for future treatments to improve or prevent cirrhosis in liver disease patients.
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
Function Of The Vitamin D Receptor In Hepatic Non-Parenchymal Cells
Funder
National Health and Medical Research Council
Funding Amount
$509,304.00
Summary
Nuclear receptors are sensors that control many aspects of metabolism, including responses to injury. Our work and has suggested that the Vitamin D Receptor (VDR) may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so, and in which cells VDR has this role. This work will provide a basis for future treatments to improve or prevent severe liver diseases.
Novel Approaches To The Pathogenesis Of Chronic Hepatitis C Virus Associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated ....The incidence of hepatitis C virus (HCV) infection is rapidly increasing in our community. This infection cannot be prevented by vaccination and the current treatments often fail. We believe that the novel approaches we are taking towards gaining an improved understanding of this disease process have the potential to lead to better therapies. We propose to examine disease progression using the new technology of gene array which scans thousands of genes simultaneously to find those most activated. Our preliminary experiments indicated that one particular set of genes related to cell death is upregulated in HCV cirrhosis more than in other kinds of cirrhosis. We propose to pursue the diagnostic-prognostic potential of one of these molecules. Primarily this project will ask what kinds of genes are activated by HCV infection and at various stages of disease progression through to fibrosis and cirrhosis and following liver transplantation to better understand these processes. We believe that this research is likely to lead to a new understanding of hepatitis C associated liver disease that may lead to novel approaches to therapy.Read moreRead less
The Role Of Fibroblast Activation Protein In Chronic Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Chronic liver diseases, particularly those caused by Hepatitis B virus and Hepatitis C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. We have identified a key molecule Fibroblast Activation Protein (FAP) that may play a key role and the process of liver fibrosis (scarring). The aims of the project are four fold: (1) ....Chronic liver diseases, particularly those caused by Hepatitis B virus and Hepatitis C virus infection, are major causes of morbidity and mortality in our community. They are characterised by progressive scarring of the liver which finally leads to liver failure and the need in many cases for organ transplantation. We have identified a key molecule Fibroblast Activation Protein (FAP) that may play a key role and the process of liver fibrosis (scarring). The aims of the project are four fold: (1) To characterise where and on what cells FAP is produced in the liver and whether FAP levels correlate with the development of fibrosis in human chronic liver diseases caused by either Hepatitis B or Hepatitis C virus infections. (2) To examine a mouse strain in which the FAP molecule is knocked out ie absent. This will tell us whether FAP itself is essential for the development of fibrosis. (3) To isolate the cells within the liver that make FAP and to examine how particular functions of these cells are modified by FAP. (4) To find out what particular molecules FAP acts upon to perform its functions. The achievement of these aims will greatly increase our understanding of this key enzyme and its role in chronic liver injury. This work can potentially lead to the development of specific inhibitors of FAP function designed to relieve liver damage.Read moreRead less
Effect Of Liver Pathophysiology On Hepatic Pharmacokinetics
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
The liver is the main organ in the body for the metabolism and biliary excretion of natural and foreign solutes. Various liver diseases such as cirrhosis, alcoholic liver disease, diet and drug induced fatty livers can affect the uptake and metabolism of drugs and their suitability- dosing needs. Some liver diseases such as fatty livers are very common but how rapidly drugs are metabolised in these patients is not well described. The work is important as it may help us better design new drugs an ....The liver is the main organ in the body for the metabolism and biliary excretion of natural and foreign solutes. Various liver diseases such as cirrhosis, alcoholic liver disease, diet and drug induced fatty livers can affect the uptake and metabolism of drugs and their suitability- dosing needs. Some liver diseases such as fatty livers are very common but how rapidly drugs are metabolised in these patients is not well described. The work is important as it may help us better design new drugs and better choose which drugs to give and, if so, in what doses. In addition, many liver diseases require a biopsy for a definite diagnosis of the likely function of the liver. Estimation of liver function is particularly important in estimating whether there will be sufficient reserve on resection of a cancer or deciding if a liver transplant is needed. The liver is also a very complex organ which can trap or breakdown solutes by a range of different systems. Also of importance is how those diseases affect drug disposition in the liver given that an altered hepatic drug disposition may affect systemic response to the drugs and their metabolites. This work seeks to answer these questions.Read moreRead less