Abstract

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMG-CoAS) is a key enzyme in ketogenesis, catalyzing the condensation of acetyl-CoA and acetoacetyl-CoA to generate HMG-CoA, which is eventually converted to ketone bodies. Transcription of the nuclear-encoded gene for mHMG-CoAS is stimulated by peroxisome proliferator-activated receptor (PPAR) , a fatty acid-activated nuclear hormone receptor. Here we show that the mHMG-CoAS protein physically interacts with PPAR in vitro, and potentiates PPAR-dependent transcriptional activation via the cognate PPAR response element of the mHMG-CoAS gene in vivo. Immunofluorescence of transiently transfected cells demonstrated that in the presence of PPAR, mHMG-CoAS is translocated into the nucleus. Binding to PPAR, stimulation of PPAR activity and nuclear penetration require the integrity of the sequence LXXLL in mHMG-CoAS, a motif known to mediate the interaction between nuclear hormone receptors and coactivators. These findings reveal a novel mechanism of gene regulation whereby the product of a PPAR-responsive gene, normally resident in the mitochondria, directly interacts with this nuclear hormone receptor to autoregulate its own nuclear transcription.