This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mitochondrial dysfunction may be responsible for the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD), a condition that affects over 71 million individuals in the U.S. alone. Impaired mitochondrial function could lead to both the initial accumulation of hepatic triglycerides via decreased oxidative disposal, as well as the transition to steatohepatitis due to enhanced oxidative stress originating from the plethora of redox reactions required for oxidative phosphorylation. As a result, we believe that there may be significant differences in mitochondrial metabolism between individuals with bland steatosis, presumed to be a benign condition, and steatohepatitis (NASH), a progressive and morbid form of NAFLD. The goal of this grant will be to use newly-developed, non-invasive, in vivo NMR-based stable isotope methodologies to define the role of hepatic mitochondrial dysfunction in the development of NAFLD and how these alterations relate to the development of insulin resistance and NASH. Such measurements are difficult or impossible to do using standard mass spectrometry techniques or classic radiotracers.
The first aim of this proposal seeks to determine if the increased rates of gluconeogenesis observed in insulin resistance and NAFLD are associated with increased energy generation via the citric acid (TCA) cycle, a component of mitochondrial function. We have observed an association between energy generation in the TCA cycle and gluconeogenesis occurring from precursors such as lactate and alanine, suggesting that these processes are energetically linked. In the second aim of this proposal we will determine if progression from bland steatosis to NASH is associated with a progressive decline in a second component of mitochondrial function, ketogenesis. Several reports demonstrate that FA synthesis in liver is inappropriately increased in subjects with NAFLD, implying that mitochondrial FA ?-oxidation is inhibited via the effect of malonyl-CoA on carnitine palmitoyl transferase. Attenuation of hepatic ?-oxidation may be associated with decreased export of ketones to the periphery in favor of local energy generation to support cellular processes in the hepatocyte. In the final aim, the ability of metformin, a proposed therapy for NAFLD, to augment hepatic mitochondrial function in individuals with NAFLD will be quantified. The benefits of the proposed research are several-fold: First, improved understanding of the metabolic derangements complicit in the pathogenesis and progression of NAFLD will allow better clinical insight and focused approaches to therapy;Second, our methodologies may provide a simple, non-invasive method to identify individuals with NASH, who are at greatest risk of progressive liver disease;and Third, a better understanding of the mechanism of action of metformin in the treatment of NAFLD will allow this therapy to be targeted to individuals most likely to derive benefit.
|Funk, Alexander M; Anderson, Brian L; Wen, Xiaodong et al. (2017) The rate of lactate production from glucose in hearts is not altered by per-deuteration of glucose. J Magn Reson 284:86-93|
|Mishkovsky, Mor; Anderson, Brian; Karlsson, Magnus et al. (2017) Measuring glucose cerebral metabolism in the healthy mouse using hyperpolarized 13C magnetic resonance. Sci Rep 7:11719|
|Moreno, Karlos X; Harrison, Crystal E; Merritt, Matthew E et al. (2017) Hyperpolarized ?-[1-13 C]gluconolactone as a probe of the pentose phosphate pathway. NMR Biomed 30:|
|Zhang, Liang; Habib, Amyn A; Zhao, Dawen (2016) Phosphatidylserine-targeted liposome for enhanced glioma-selective imaging. Oncotarget 7:38693-38706|
|Malloy, Craig R; Sherry, A Dean (2016) Biochemical Specificity in Human Cardiac Imaging by 13C Magnetic Resonance Imaging. Circ Res 119:1146-1148|
|Wu, Yunkou; Zhang, Shanrong; Soesbe, Todd C et al. (2016) pH imaging of mouse kidneys in vivo using a frequency-dependent paraCEST agent. Magn Reson Med 75:2432-41|
|Walker, Christopher M; Merritt, Matthew; Wang, Jian-Xiong et al. (2016) Use of a Multi-compartment Dynamic Single Enzyme Phantom for Studies of Hyperpolarized Magnetic Resonance Agents. J Vis Exp :e53607|
|Moss, Lacy R; Mulik, Rohit S; Van Treuren, Tim et al. (2016) Investigation into the distinct subcellular effects of docosahexaenoic acid loaded low-density lipoprotein nanoparticles in normal and malignant murine liver cells. Biochim Biophys Acta 1860:2363-2376|
|Xing, Yixun; Jindal, Ashish K; Regueiro-Figueroa, Martín et al. (2016) The Relationship between NMR Chemical Shifts of Thermally Polarized and Hyperpolarized 89 Y Complexes and Their Solution Structures. Chemistry 22:16657-16667|
|Jin, Eunsook S; Moreno, Karlos X; Wang, Jian-Xiong et al. (2016) Metabolism of hyperpolarized [1-(13)C]pyruvate through alternate pathways in rat liver. NMR Biomed 29:466-74|
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