Data di Pubblicazione:
2010
Citazione:
EFFECTS OF HISTONE DEACETYLASE INHIBITORS ON ENERGY METABOLISM / A. Galmozzi ; Tutor: Emma De Fabiani ; Coordinatore: Francesco Bonomi. Universita' degli Studi di Milano, 2010 Dec 09. 23. ciclo, Anno Accademico 2010. [10.13130/galmozzi-andrea_phd2010-12-09].
Abstract:
Type 2 diabetes mellitus (T2DM) is the most common metabolic disease in the world. Maintenance of glucose homeostasis depends on a complex interplay between the insulin responsiveness of skeletal muscle, liver, adipose tissue and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in these organs are responsible for insulin resistance and progression to hyperglycemia.
Understanding the integrated pathophysiology initiating the development of insulin resistance should extend our capacity to identify novel therapeutic targets for the prevention and/or treatment of T2DM. This biology remains incompletely characterized, in part, due to the interaction of multiple organ systems. The complexity of this biology is further underscored by the progressive changes in the systemic milieu including the onset of hyperinsulinemia, elevated circulating free fatty acids and triglycerides, hyperglycemia, and the activation of systemic immune system during the development of T2DM.
In skeletal muscle, loss of mitochondrial function is evident in some insulin-resistant subjects years before they develop diabetes. Mitochondria are particularly important for skeletal muscle function, given the high oxidative demands imposed on this tissue by intermittent contraction. Moreover, muscle cells must maintain metabolic flexibility, defined as the ability to rapidly modulate substrate oxidation as a function of hormonal and energetic conditions.
The molecular mechanisms that control mitochondrial number and function remain poorly understood, and only a few transcription factors or coactivators (e.g., PGC-1α, NRF1, Tfam) have been associated with this process. Notably, skeletal muscle differentiation and remodelling are also controlled at the epigenetic level, via transcriptional modulation of key genes in mitochondrial biogenesis and oxidative metabolism, involving enzymes, such as members of the histone deacetylase (HDAC) family, in particular those belonging to class I and class II, which modulate post-translational modifications on target proteins. The current knowledge on HDACs is that they function in general as transcriptional repressors, however their role in vivo is likely more complex. Less is known on the effects of HDACs modulators on energy metabolism, however a recent study reported that supplementation with sodium butyrate, a dietary component active as HDAC inhibitor, promotes energy expenditure and mitochondrial function in mice fed with a high fat diet212. Given the importance of skeletal muscle metabolism in insulin resistance/diabetes, and given the role of HDACs in skeletal muscle biology, it is reasonable to speculate that modulation of these enzymes would play a role in this pathology that deserves to be investigated more deeply.
Based on the evidences that mitochondrial dysfunction is often associated to whole body metabolic dysregulation, aim of this study is to better understand the role of histone deacetylases in the regulation of mitochondrial biogenesis and in the modulation of all these mechanisms underlying the pathophisiology of insulin resistance.
In C2C12 myotubes treated with pan and class selective HDAC inhibitors (HDACi), such as SAHA(pan-inhibitor), MS275 (Class I HDAC inhibitor) and MC1568 (Class II HDAC inhibitor), transcriptome analysis revealed an increase of OXPHOS genes and of genes encoding fatty acid catabolic enzymes, following treatment with pan or class I HDACi. Moreover, staining of myotubes treated with SAHA and MS275 showed an increase of mitochondrial density and activity, coupled with an increase in mitochondrial DNA content.
In Db/Db obese and diabetic mice we observed that treatments with SAHA and MS275 reduce glycemia, triglycerides, plasma insulin land transaminases levels and i
Tipologia IRIS:
Tesi di dottorato
Keywords:
energy metabolism ; histone deacetylases ; mitochondria ; type II diabetes
Elenco autori:
A. Galmozzi
Link alla scheda completa:
Link al Full Text: