Biochemistry, Department of
TRANSCRIPTOMIC ANALYSES AND COMPUTATIONAL MODELING REVEAL THAT FATTY ACID TRANSPORT PROTEIN 2 (FATP2) IMPACTS THE TRANSCRIPTIONAL ACTIVITY OF PPARα THUS ALTERING THE LIPID METABOLIC LANDSCAPE
Paul N. Black
Date of this Version
Fatty acid transport protein 2 (FATP2) is highly expressed in liver, small intestine, and kidney where it functions in both the uptake of exogenous long chain fatty acids (LCFAs) and in the activation of very long chain fatty acids (VLCFAs). Here we address the phenotypic impacts of deleting FATP2 with the following three separate approaches:  Utilizing an unbiased next-generation sequencing analysis of FATP2-null (fatp2-/-) mice fed a standard chow diet;  Utilizing an unbiased next-generation sequencing analysis of fatp2-null (fatp2-/-) mice fed a high-fat ketogenic diet (KD) and fasted for 24-hours  Building dynamic computer models built with data acquired from approaches one and two.
The findings from our first approach wild type (C57BL/6J) and FATP2 null (fatp2-/-) mice (5 weeks old) were maintained on a standard chow diet for 6 weeks (11 weeks old). Initial characterization revealed that fatp2-/- mice had reduced weight gain and dietary fatty acid absorption. The male fatp2-/- mice had 258 differentially expressed genes (DEGs) and the female mice had a total of 91. Of significance was the finding that most DEGs from the fatp2-/- liver are regulated by the transcription factor peroxisome proliferator-activated receptor alpha (PPARα). In our second approach, we found the fatp2-/- mice had reduced body weights on both control diet (CD) and KD diets, but dietary changes did not reduce the fatp2-/- weight further. DEGs from liver tissue of mice fed a KD mapped to ontologies like amino acid metabolism, complex I biogenesis, innate immune response, cytokine signaling, and adaptive immune system, and were supported by the proteomic analysis and histological staining. Of significance was finding DEGs and proteins up-regulated belong to amino acid degradation pathways, possibly indicating lipid reserves are depleted in the fatp2-/- on KD. Finally, in our third approach we provided 6 new Mus musculus genome-scale metabolic models (GEMs) specific to the c57bl6 strain liver-tissue on three diets. These diets include a standard chow, control-ketogenic diet (CD), and KD. These simulations show that when fatp2 is removed the sum of the flux in the branched chain amino acid metabolism is increased.
Advisors: Paul N. Black and Tomas Helikar
A Dissertation Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy, Major: Biochemistry (Bioinformatics), Under the Supervision of Professors Paul N. Black and Tomas Helikar. Lincoln, Nebraska: November 2019.
Copyright (c) 2019 Vincent M. Perez