Metabolomics Consortium Collaborative Webinar Series

This webinar series highlights the collaborative projects of metabolomics research investigators and their biomedical collaborators with the intention of engaging scientists within other NIH institutes, as well as presenting case studies to the consortium of successful metabolomics partnerships.

June 17, 2021 @ 2pm EST

Mechanisms Regulating Mitochondrial Oxidative Function in the Liver

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Speakers

Nishanth Sunny

University of Maryland

Tim Garrett

University of Florida

Nonalcoholic fatty liver disease (NAFLD) is prevalent in over 70% of the obese and type II diabetes mellitus (T2DM) patients and is a leading cause of liver transplantation.  Hepatic insulin resistance and inflammation mirror alterations in mitochondrial oxidative flux (beta-oxidation, tri-carboxylic acid [TCA] cycle, ketone turn over and mitochondrial respiration), in rodent models and humans with simple steatosis and steatohepatitis. Our objective is to identify mechanisms leading to dysfunctional mitochondrial oxidative flux and development of hepatocellular stress and inflammation during NAFLD. We hypothesize that the severity of hepatocyte inflammation and reactive oxygen species (ROS) generation will be proportional to the rates of mitochondrial oxidative flux. Thus, attenuation of oxidative flux will be a promising strategy to alleviate inflammation and hepatocellular stress during NAFLD. Towards our overarching objective, we are providing evidence on the following three areas. 1) The impact of dietary macronutrient compositions (high fat versus high fat/high fructose) on the remodeling of mitochondrial oxidative function during the onset of NAFLD. 2) The interactions between branched chain amino acids (BCAAs; which are robustly indicators of insulin resistance), mitochondrial oxidative function and lipogenesis. 3) The impact of a clinically relevant polymorphism in the NADH dehydrogenase subunit 2 (mt-Nd2^A) allele towards attenuating mitochondrial oxidative dysfunction during NAFLD. State-of-the-art metabolic profiling techniques (flux analysis and metabolomics) in nuclear magnetic resonance and mass spectrometry are combined to determine changes in mitochondrial oxidative function and lipogenesis. In conclusion, our studies provide clear evidence on how identifying key mechanisms, which remodel mitochondrial oxidative flux, will provide a better paradigm to treat NAFLD by alleviating hepatocellular stress and inflammation.