6 Fat accumulates in liver hepatocytes with toxic effects including the inflammation and fibrosis seen in NASH. 6 As a result of the mutation, called PNPLA3 I148M, a dysfunctional liver enzyme is produced that is not only unable to digest fat itself, but impedes another type of enzyme from doing it too. It takes just a single nucleotide substitution in the PNPLA3 gene to severely impair normal fat breakdown in liver cells.
Underpinning these benefits were suppression of lipid production in the liver and improved mitochondrial activity, indicative of enhanced metabolic function.Ĭlinical studies are now underway to investigate the treatment effects on liver function, glucose levels and weight loss in patients with NASH. 12 In these models of disease, it reduced steatosis and inflammation, reversed fibrosis, improved glucose control, decreased food intake and induced weight loss. Newly published research in Nature Metabolism showed that our candidate dual GLP-1R/GcgR agonist has beneficial effects in preclinical NASH models. 11 Glucagon receptors are found in the liver where activation results in increased energy expenditure and reduced lipid production. GLP-1 receptors are found mainly in the brain and pancreas, and activation results in beneficial effects on food intake, insulin secretion and weight loss. 10 This is designed to improve metabolic function by working like the intestinal hormone, oxyntomodulin, which is known to decrease food intake and increase energy expenditure, leading to weight loss in overweight and obese individuals. In the LITMUS consortium in Europe, there is a major focus on development of pre-clinical models and patient-reported outcome tools for NASH with the aim of using them in future studies.Ī promising potential medicine in development at AstraZeneca is a dual agonist of the glucagon-like protein-1 and glucagon receptors (GLP-1R/GcgR). Through our leadership role in the US-based NIMBLE consortium, we are working towards enhancing the quality of our NASH clinical trials, all of which include in-depth analysis of soluble and imaging biomarkers for NASH diagnosis. We are actively engaged in two major public-private partnership consortia that are testing non-invasive tools for NASH diagnosis that may in the future be used as endpoints in clinical trials of potential new medicines. However, only a liver biopsy can show inflammation, severity of fibrosis and other signs of liver damage, and confirm a diagnosis of NASH. In its early stages, NASH may be largely silent, with patients unaware they have the disease.Ībnormal blood test results including raised levels of liver enzymes may suggest NASH, and ultrasound or MRI scans can show fat in the liver and liver stiffness. Through our investment in a cell therapy department and commitment to studying the mechanisms of regeneration, we are exploring the potential of replacing diseased liver tissue with the aim of restoring liver health.īy targeting multiple mechanisms, we are developing a combination approach to the treatment of NASH and associated cardiovascular and renal diseases with the bold ambition of reversing the current upward trends in morbidity and mortality. 5 By silencing these mutations, our goal is to interrupt key NASH mechanisms.
Such advances also have implications for alleviating type 2 diabetes, as well as cardiovascular and renal diseases, since emerging science suggests significant ‘cross-talk’ between the liver and other organs.Īt the forefront of precision medicine research, we are targeting genetic mutations associated with NASH, which are responsible for an approximately four-fold increase in risk of the disease. Through our metabolic research programmes, we are developing promising approaches for reducing liver fat and inflammation, with the ambition of halting or reversing progression of fibrosis and irreversible liver damage. 3 People with NASH are also at greater risk of type 2 diabetes and cardiovascular disease. 1 It is rapidly becoming a leading cause of chronic liver disease 2 and a reason for liver transplantation. Non-alcoholic steatohepatitis, or NASH, is a liver disease in which a build-up of fat in the liver is followed by inflammation and cell damage. Partnerships, alliances and recognition.
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