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What is the role of caspase-2 mediated lipoapoptosis in the pathogenesis of the metabolic syndrome-associated liver disease, nonalcoholic fatty liver disease (NAFLD)?
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Resumo(s)
Nonalcoholic fatty liver disease can be considered the hepatic manifestation of obesity and the metabolic syndrome. It is the number one cause of chronic liver disease in the Western world. Lipotoxicity in the liver induces epithelial lesion that triggers a wound healing response. In susceptible subjects the wound healing response is ineffective in repairing and regenerating the injured liver, leading to scarring, fibrogenesis and eventually hepatic cirrhosis. Though important advances in the knowledge of the pathogenesis of NAFLD have occurred since its firsts descriptions in 1980, gaps in knowledge still precludes Hepatologists to find an effective treatment for this pandemic.
We first extensively characterized and compared two dietary mouse models of NAFLD, methionine-choline deficient (MCD) and Western diets. We found that MCD diet induces severe disease with significant fibrosis, whereas Western diet induces mild disease, but associates with obesity, insulin resistance and the metabolic syndrome.
Afterwards, we demonstrated a pivotal role of caspase-2 in the development of the metabolic syndrome, NAFLD, progression to severe liver disease and hepatic fibrogenesis.
Caspase-2 was up-regulated in human NAFLD and in in several different mouse models of NAFLD, correlating with the degree of fibrosis. Also, caspase-2 deficient mice were protected from the metabolic syndrome and liver injury/fibrosis in both MCD and Western diet mouse models.
Finally, we found that in different mouse models of NAFLD, hepatic free coenzyme A content is decreased, which could potentiate caspase-2 activation. We conducted a preclinical trial in mice submitted to MCD diet, treating them with coenzyme A precursors. This approach failed to correct hepatic free coenzyme A levels and had no impact in liver histology or caspase-2 expression/activation.
Our work places caspase-2 as a potential therapeutic target for obesity-associated diseases, such as type 2 diabetes mellitus and NAFLD.
Descrição
Palavras-chave
NAFLD fibrosis metabolic syndrome caspase-2 coenzyme A FGNA fibrose síndroma metabólico coenzima A