HNF4 was originally classified as an orphan receptor that exhibits constitutive transactivation activity apparently by being continuously bound to a variety of fatty acids. The existence of a ligand for HNF4 has been somewhat controversial, but linoleic acid (LA) has been identified as the endogenous ligand of native HNF4 expressed in mouse liver; the binding of LA to HNF4 is reversible.
The ligand binding domain of HNF4, as with other nuclear receptors, adopts a canonical alpha helical sandwich fold and interacts with co-activator proteins.
HNF4 binds to the consensus sequence AGGTCAaAGGTCA in order to activate transcription.