Abstract
The peroxisome proliferator‐activated receptor gamma coactivator 1α (PGC‐1α) is a transcriptional coactivator that plays a key regulatory function in mitochondrial biogenesis and lipid metabolism. It is highly induced upon cold exposure in brown fat, exercise in skeletal muscle and fasting in liver. The function of PGC‐1α has been extensively studied, but not much is known about how PGC‐1α activity is regulated. In order to identify novel PGC‐1α modulators, we characterized novel interacting molecules from nuclear liver extracts via biochemical purification followed by mass‐spectrometry analysis. Among a number of interactors we chose to study ACOX1 (Acyl Coenzyme A Oxidase). ACOX1 is the first and rate‐limiting enzyme of the peroxisomal fatty acid β‐oxidation and its expression is known to be under the control of PPARα, a transcription factor involved in fatty acid metabolism, potently coactivated by PGC‐1α. By in vitro pull‐down assay and by co‐immunoprecipitation in Hek293 cells, we reconfirmed that PGC‐1α interacts with ACOX1. ACOX1 is able to increase the transcriptional activity of the PGC‐1α/PPARα complex in luciferase assays. These results suggest that ACOX1 is able to modulate its own expression by enhancing the activity of its own transcriptional regulator PGC‐1α, creating a positive feedback loop that regulates lipid metabolism.Supported by the Intramural Research Program of NIDDK, NIH.
Published Version
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