Assessing Diagnostic and Therapeutic Targets in Obesity-Associated Liver Diseases

Identifier:  TDX:2963

Handle: https://hdl.handle.net/20.500.11797/TDX2963

Authors:  Cabré Casares, Noemí

Abstract:
Hepatic alterations, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are frequently associated with obesity. The absence of non-invasive markers for NASH diagnosis hampers clinical practice and the development of pharmacological treatments. In order to investigate the molecular mechanisms of these alterations and to identify molecules that could be used as potential therapeutic targets we search for noninvasive biomarkers of liver alterations in patients type III obesity undergoing bariatric surgery (BS). In our first study we showed that the liver function of patients with obesity are significantly improved after BS through mechanisms that involve the reduction of oxidative stress and inflammatory processes. In the second study we performed measurements in obese patients undergoing BS to identify specific metabolic patterns and to test the diagnostic ability to distinguish between patients with and without NASH. Targeted plasma metabolic profiles identified connections between liver metabolism and morbid obesity. Combined models of single or paired plasma measurements of alpha-ketoglutarate, beta-hydroxybutyrate, pyruvate and oxaloacetate reduced the uncertainty in clinical diagnosis of NASH and predicted NASH remission. In the third study we demonstrated that alpha-ketoglutarate is a key metabolite of energy homeostasis that modulates hepatocyte death in NASH patients through mammalian TORC1 (mTORC1). After BS, the mitochondrial oxidative metabolism and the autophagy-lysosomal function compromised in NASH patients, were also completely restored. AMPK activation in hepatocytes abrogated the effects of glutaminolysis supports the potential use of mTORC1 inhibitors. Finally, we confirm that metabolites may promote epigenetic changes affecting DNA methylation and likely post-translational modifications on enzymes regulating liver energy metabolism. Oxidative stress, mitochondrial dysfunction and cell death responses are implicated in NAFLD diseases via metabolic reprogramming. In conclusion, alpha-ketoglutarate could be a new potential biomarker and therapeutic strategy of NASH.