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Grants and Contracts Details
Description
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.
Status | Finished |
---|---|
Effective start/end date | 6/15/22 → 12/31/22 |
Funding
- National Institute of General Medical Sciences
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Projects
- 1 Finished
-
University of Kentucky Center for Cancer Metabolism (Admin Core)
Zhou, B. (PI), Arnold, S. (CoI), Brainson, C. (CoI), Cassis, L. (CoI), D'Orazio, J. (CoI), Evers, B. M. (CoI), Fan, W.-M. (CoI), Fong, K. W. (CoI), Hersh, L. (CoI), Higashi, R. (CoI), Jia, J. (CoI), Lane, A. (CoI), Liu, J. (CoI), Liu, X. (CoI), Liu, X. (CoI), Marcinkowski, E. (CoI), Moseley, H. (CoI), Rellinger, E. (CoI), Stromberg, A. (CoI), Thorson, J. (CoI), Van Eldik, L. (CoI), Vanderford, N. (CoI), Wang, C. (CoI), Weiss, H. (CoI), Wu, Y. (CoI), Xu, R. (CoI), Zhu, C. (CoI), St Clair, D. (CoPI), Gentry, M. (Former CoI), Hildebrandt, G. (Former CoI) & Wang, P. (Former CoI)
National Institute of General Medical Sciences
3/1/17 → 12/31/22
Project: Research project