H2020Индивидуална стипендия2016–2018

EXNADMINA · EXercise as a regulator of hepatic NAD metabolism and MItochondrial function in Non-Alcoholic fatty liver disease

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2016-09-01 → 2018-02-28
Финансиране от ЕС: 146 591 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Физическата активност и нивата на NAD се изследват при мишки с мазен черен дроб, за да се разбере влиянието им върху работата на митохондриите. Това е важно, защото заболяването често води до възпаления, цироза или рак на черния дроб.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

EXercise as a regulator of hepatic NAD metabolism and MItochondrial function in Non-Alcoholic fatty liver disease

Non-alcoholic fatty liver disease, a disorder which is associated with obesity, has become the most prevalent liver disease in industrialized countries, including Europe. Fatty liver disease comprises a spectrum of disorders ranging from hepatic fat accumulation (steatosis) to inflammation (non-alcoholic steatohepatitis) and fibrosis. In approx. 10% of patients this in turn leads to liver failure or the development of liver cancer (hepatocellular carcinoma) later in life. Apart from severely restricting personal health and wellbeing, the later stages of fatty liver disease also lead to substantially increased healthcare-related costs. The development of fatty liver disease and other metabolic disorders has been associated with a decline in cellular levels of NAD which is both an essential cofactor for cellular energy production from different nutrients and a substrate of enzymes that regulate energy metabolism. Experiments with mice with obesity and fatty liver disease induced by a diet high in fat show that supplementing NAD using NAD precursors which belong to the vitamin B3 group has beneficial effects on cellular metabolism and can counteract the negative effects of a high fat diet. Cellular organelles called mitochondria are mainly responsible for cellular energy production and are dependent on the correct levels of NAD and its derivative NADP. An enzyme which is essential in regulating mitochondrial NAD and NADP termed Nnt (nicotinamide nucleotide transhydrogenase) does not function in commonly used laboratory mice due to a mutation. These mice show defects in mitochondrial function but have been used almost exclusively in studies examining the effects of NAD supplementation in obesity and fatty liver disease. We hypothesized that mice having this non-functional version of Nnt will respond differently to a high fat diet and NAD supplementation compared to mice with a functional version of this enzyme. The aim of this project was to evaluate these two different, but commonly used mouse strains (with and without functional Nnt). By addressing this fundamental question we aimed to provide knowledge useful for the interpretation of mouse experiments in the field of obesity research and associated diseases and at the same time shed light on the manner how obesity and fatty liver disease develop and which mechanisms are involved.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in industrialized countries, including Europe, and comprises a spectrum of disorders ranging from hepatic lipid accumulation (steatosis) to inflammation (non-alcoholic steatohepatitis, NASH) and fibrosis. Pathogenic pathways leading from hepatic steatosis to NASH are still incompletely understood resulting in a lack of approved therapeutic options besides life style changes. Physical activity is effective to prevent NAFLD progression. The mechanism of exercise action on liver mitochondrial metabolism is not clear yet. However, exercise might exert its positive effects via increasing hepatic nicotinamide adenine dinucleotide (NAD) levels. Several studies showed that the hepatic NAD metabolism is dysregulated during the development of NAFLD and that exercise has a positive effect on NAD metabolism and function of NAD dependent enzymes in skeletal muscle. The functionality of mitochondrial metabolism is highly dependent on the maintenance of the organellar NAD pool. Mitochondrial dysfunction has been implicated in the progression from steatosis to NASH. We hypothesize that a dysregulated NAD metabolism in the liver is involved in the development of hepatic mitochondrial dysfunction in NAFLD/NASH. Our overall aim is to define the impact of exercise on hepatic mitochondrial dysfunction and test whether exercise effects are mediated via restoration of NAD metabolism. We will achieve this by combining the knowledge on hepatic NAD metabolism of the fellow with the expertise in exercise mouse models and on analysis of mitochondrial function of the Supervisor. This study is one of the first to comprehensively examine the interaction between exercise, mitochondrial dysfunction as a cause of NAFLD and NAD metabolism specifically in the liver and in hepatocytes and ultimately aims to identify novel therapeutic targets for the prevention and treatment of NAFLD.

Оригинален текст от CORDIS (на английски).

Участници

THE UNIVERSITY OF BIRMINGHAM · BirminghamКоординаторОбединеното кралство