Abstract 17822: Impairment of the PPARa/PGC1a Axis Compromises Mitochondrial Biogenesis and Function in Hearts With Cardiomyocyte-Specific Fatty Acid Transport Protein 1 (FATP1) Overexpression
Background: PPARα and PGC1α are critical regulators of myocardial metabolism that promote fatty acid oxidation and mitochondrial biogenesis. Both PPARα and PGC1α are upregulated in metabolic diseases such as obesity and type 2 diabetes that are characterized by pathologically increased cardiomyocyte free fatty acid (FFA) uptake and accumulation mediated, in part, by the long-chain fatty acid transport protein, FATP1. Cardiomyocyte-specific overexpression of FATP1 increases myocyte FFA 2-fold and is associated with diastolic dysfunction. We hypothesized that FATP1-mediated FFA accumulation would upregulate PPARα and PGC1α, and increase mitochondrial biogenesis/function.
Methods: Cardiac mitochondria, whole-heart protein and RNA were isolated from 5-8-week old FATP1 and WT mice. PPAR-related gene expression was evaluated via PCR array and quantitative RT-PCR, protein expression by immunoblotting, mitochondrial morphology by electron microscopy, and mitochondrial respiration using a Seahorse XF24 analyzer.
Results: Contrary to expectations, in FATP1 hearts there were marked decreases in PPARα (-50%, p<0.05) and PGC1α (-45%, p<0.01) mRNA. These changes were associated with a marked decrease in mitochondrial size (-49%, p<0.01) and reductions in electron transport chain complex I (-44%, p<0.01) and complex II (-31%, p<0.01) protein expression. Functionally, FATP1 over-expression was associated with decreased mitochondrial complex II substrate-driven state III respiration (-33%, p<0.05), and decreased activity of electron transport chain (ETC) complex I (-22%, p<0.01) and complex II (-62%, p=0.05).
Conclusions: Cardiomyocyte FATP1 overexpression leading to FFA accumulation results in a paradoxical decrease in PPARα and PGC1α expression, with concomitant impairment in mitochondrial biogenesis, ETC complex protein expression/activity, and respiration. Excessive delivery of FFA to the cardiac myocyte, per se, in the absence of systemic metabolic disorders, leads to down-regulation of PPARα and PGC1α that likely contribute to impaired mitochondrial biogenesis and function.
- © 2013 by American Heart Association, Inc.