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The effects of aerobic exercise on hepatic MTCH2 expression/function: a study from bench-to-bedside for NAFLD control

Abstract

The non-alcoholic fatty liver disease (NAFLD) may contribute to the development of insulin resistance and diabetes and, when untreated, can progress to damage to the tissue itself such as fibrosis, cirrhosis, carcinoma and, in more severe cases, organ failure. In this sense, the knowledge of therapeutic strategies for the reduction of liver fat accumulation is crucial. Physical exercise is an important non-pharmacological tool for the treatment of NAFLD. On the other hand, how this practice has its benefits in fat accumulation in the liver are not yet fully known. Recently, it was shown that animals that overexpress globally Mitochondrial Carrier Protein Homolog 2 (MTCH2) presented liver mitochondrial dysfunction and, consequently, greater accumulation of fat in the tissue and hyperglycemia. Thus, it is evident that MTCH2 has actions in the hepatic lipogenic process, however, the way that the lipogenesis occurs in the organ is not fully elucidated. In addition, no study has been carried out in order to show whether the beneficial effects of exercise in reducing NAFLD are mediated by MTCH2. Thus, the aim of this research project will be to translationally and tissue-specific investigate the role of MTCH2 in the process of hepatic lipogenesis and, further, investigate whether the reduction of NAFLD triggered by exercise is mediated by MTCH2 in both cells and rodents as well as in humans. For this purpose, initially, to understand the MTCH2-mediated hepatic lipogenic process, the protein gene will be deleted or overexpressed in palmitate-treated HepG2 cells. After that, to understand if the effects of physical exercise on reducing NAFLD are mediated by hepatic MTCH2, HepG2 cells (knockout or overexpressed for MTCH2 and treated with palmitate) will be treated with serum from obese mice that were submitted to a short-term aerobic exercise. In the next step, obese mice and MTCH2 knockouts in the liver (MTCH2F/F Alb-Cre mice) will undergo a short-term aerobic exercise protocol. The choice of short-term exercise protocol is to observe the direct effects of exercise and there are no effects of body weight reduction that could directly influence the NAFLD. Finally, to understand whether the findings found in cells and rodents are likely to be transported to humans, initially, liver tissue aliquots from healthy, obese, and obese humans diagnosed with NAFLD will be cultured directly. The samples will then have the MTCH2 gene deleted or overexpressed, for the subsequent treatment with serum from short-term exercised obese human. At the end of each study (immortalized cells, rodents, and humans), accurate techniques to evaluate the behavior of hepatic MTCH2 on NAFLD will be used, such as: fat liver quantification, biomolecular pathways (lipogenic, oxidative, inflammatory, insulin, apoptotic, and endoplasmic reticulum stress), hepatic and mitochondrial function and lipidomic and proteomic analysis. At the end of the project, if our hypothesis is confirmed, it is expected to be able to list the liver MTCH2 as an important therapeutic target for the NAFLD treatment. And then, in the near future, opening the possibility of creating mimetic agents to exercise (synthetic or nutritional) to reduce the activity of MTCH2 in liver tissue and, consequently, improving the hepatic health of diabetic patients. (AU)

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