| Summary: |
Rational: Obesity is a worldwide epidemic with collateral diseases, including liver damage. Data report that obesity and liver dysfunction are associated with increased levels of oxidative damage, inflammation and apoptosis, involving mitochondria in the process. Our group with the support of FC T (PTDC /DES/113580/2009) recently studied this topic [1-4]. However, new data highlighted that endoplasmic reticulum (ER) stress is also a central regulator in nonalcoholic fatty liver disease, including in nonalcoholic steatohepatitis (NASH). The imbalance between cellular protein folding needs and the capacity of the ER to deal with it, induces ER stress and an unfolded protein response (UPR) [5]. Recent data suggest that signaling of the NASH-related UPR is linked to oxidative stress and inflammation by various mechanisms [6] and exacerbated by visceral fat-derived cytokines
secretion [7]. Moreover, a cooperative link between ER and mitochondria in the establishment and regulation of calcium homeostasis, oxidative stress and apoptosis in several physiopathological conditions, including liver dysfunction through mitochondria-associated endoplasmic reticulum membranes (MAMs) has also been described [8]. Many strategies have been explored against NASH-related cellular disturbances, including exercise. In fact, the effects of exercise in modifying key proteins of the hepatic metabolism in obesity should not be taken lightly [9, 10]. However, if the exercise benefits in the liver in the context of obesity-related NASH may also be related with the modulation of ER function remains scarcely studied.
Aim: To analyze the effects of voluntary physical activity (VPA) and endurance training (ET) against ER stress in obesity-induced NASH, and to better comprehend the crosstalk between mitochondria and ER in this obesity-related liver disease.
Experimental setup justification: As exercise is an effective preventive and therapeutic strategy against deleterious conditions in sever  |
Summary
Rational: Obesity is a worldwide epidemic with collateral diseases, including liver damage. Data report that obesity and liver dysfunction are associated with increased levels of oxidative damage, inflammation and apoptosis, involving mitochondria in the process. Our group with the support of FC T (PTDC /DES/113580/2009) recently studied this topic [1-4]. However, new data highlighted that endoplasmic reticulum (ER) stress is also a central regulator in nonalcoholic fatty liver disease, including in nonalcoholic steatohepatitis (NASH). The imbalance between cellular protein folding needs and the capacity of the ER to deal with it, induces ER stress and an unfolded protein response (UPR) [5]. Recent data suggest that signaling of the NASH-related UPR is linked to oxidative stress and inflammation by various mechanisms [6] and exacerbated by visceral fat-derived cytokines
secretion [7]. Moreover, a cooperative link between ER and mitochondria in the establishment and regulation of calcium homeostasis, oxidative stress and apoptosis in several physiopathological conditions, including liver dysfunction through mitochondria-associated endoplasmic reticulum membranes (MAMs) has also been described [8]. Many strategies have been explored against NASH-related cellular disturbances, including exercise. In fact, the effects of exercise in modifying key proteins of the hepatic metabolism in obesity should not be taken lightly [9, 10]. However, if the exercise benefits in the liver in the context of obesity-related NASH may also be related with the modulation of ER function remains scarcely studied.
Aim: To analyze the effects of voluntary physical activity (VPA) and endurance training (ET) against ER stress in obesity-induced NASH, and to better comprehend the crosstalk between mitochondria and ER in this obesity-related liver disease.
Experimental setup justification: As exercise is an effective preventive and therapeutic strategy against deleterious conditions in several tissues, VPA on free wheel and ET in treadmill will be considered in this project. High fat diets (HFD) have been successfully used to induce NASH in rats and to study obesity-related liver dysfunction [1-4, 9]. This "ecological" dietary model (11] mimics the Western-style diet, and will be used in this study.
Repercussions of the work and hypothesis: An important contribution to elucidate the ER mechanisms associated with the possible role of exercise in the prevention of ER stress in obesity-induced NASH will be provided. Our hypothesis is that, in an obesity setting, an active life-style decreases liver ER stress, oxidative stress and subsequent, inflammation and apoptosis, resulting in decreased hepatic damage. Moreover, it is our belief that a positive cross-talk between mitochondria and the ER will be involved in this protective phenotype. Therefore, physical activity should likely be advised in patients with NASH.
Experimental Approach: Sets of wild type rats will be assigned into the following six groups: sedentary, sedentary diseased (rats fed with a HFD), active (32 wks VPA or 12 wks ET) and active diseased (fed with a HFD and submitted to VPA or ET). NASHrelated liver morphological alterations will be evaluated by light and electron microscopy. Using polymerase chain reaction and western blotting (WB), the expression of genes and the content of some proteins from the three branches of the UPR - inositol requiring enzyme (IRE-1α), activating transcription factor 6 (ATF6), and PKR-like ER-associated protein kinase (PERK) will be
assayed. Proteins involved in the infla |