Fibrate Mechanism of Action - The Center for Cholesterol Management

Fatty Acid Gene Transcription
1
Signal Transduction
Cascade
NR = Nuclear receptor or transcription factor
6
FA
FA-Co-A
FA metabolite
2
NR
Ligand Binding
NR
FARE
NR NR
FA Responsive
Gene
3
AAA
NR mRNA
5
7
Protein involved in
FA transport or
metabolism
4
NR gene
NR
NR synthesis
Duplus E et al. J Biol Chem 2000;275:30749-30552
The FA per se, FA-CoA, or FA metabolite modulate (±) transcription of a responsive gene, encoding a
protein involved in FA transport or metabolism, through various non-mutually selective potential
mechanisms. Step 1, a signal transduction cascade is initiated to induce a covalent modification of a
NR, thereby modifying its transcriptional potency. Step 2, the FA itself or its derivative acts as a
ligand for a NR, which then can bind DNA at a FA response element (FARE) and activate or repress
transcription. Steps 3, 4, and 5, FA can act indirectly via alteration in either NR mRNA stability (Step
3) or gene transcription (Step 4), resulting in variations of de novo NR synthesis (Step 5) with an
impact on the transcription rate of genes encoding proteins involved in FA transport or metabolism.
On binding to the cognate response element, NR acts either as a monomer (Step 6), a homodimer, or
a heterodimer with NR, a different NR (Step 7).