Pilot: Novel Role of the Metabolic Hormone Neurotensin on Liver Lipid Metabolism and Pathophysiology

Abstract: Non-alcoholic fatty liver (NAFLD) is the most common chronic liver disease in the world, affecting about 80 million adults in the US. NAFLD is predominantly caused by obesity and can progress to a clinically aggressive form, non-alcoholic steatohepatitis (NASH), which can subsequently progress to life threatening complications such as cirrhosis and liver cancer. Recent studies indicate that NAFLD is mediated by defective mitochondrial metabolism of fatty acid (FA), due to reduced oxidative phosphorylation (OXPHOS). However, the factors that cause defective OXPHOS function in NAFLD are currently unknown. The overall objective of this proposal is to determine: (i) how neurotensin (NT), an intestinal hormone, causes mitochondrial dysfunction in the liver by downregulating OXPHOS (Aim 1); and, (ii) how NT regulates the hepatic reactive oxygen species (ROS) balance and contributes to oxidative stress and cellular damage (Aim 2). Our preliminary studies show that NT directly reduces mitochondrial bioenergetic reserve, OXPHOS complex protein expression and mitochondrial ROS generation in the liver, thereby contributing to mitochondrial dysfunction. Conversely, NT increases cytoplasmic ROS levels and oxidative stress, implicating an indirect mechanism for ROS generation. We will isolate primary hepatocytes from the livers of Ntr1+/+ and Ntr1-/- mice fed high fat diet to analyze mitochondrial dysregulation by NT, using state of the art approaches like SIRM (Stable Isotope-Resolved Metabolomics) and Seahorse extracellular flux analyzer. Results of this pilot project will: (i) establish the role of NT as a novel metabolic hormone that contributes to the regulation of mitochondrial function and lipid metabolism, (ii) provide critical insights into the role of NT in the development of NAFLD and NASH, and (iii) facilitate development of NT-targeted therapeutics for NASH, for which there are no currently-approved therapies. Moreover, we anticipate that additional data obtained from this pilot COBRE project will serve as the basis for a new NIH application focused specifically on the novel effects of NT on liver mitochondrial function and metabolism as an etiology for NAFLD and NASH.