Mode of Peroxisome Proliferator-Activated Receptor γ Activation by Luteolin

Abstract

The peroxisome proliferator-activated receptor ␥ (PPAR␥) is a target for treatment of type II diabetes and other conditions. PPAR␥ full agonists, such as thiazolidinediones (TZDs), are effective insulin sensitizers and anti-inflammatory agents, but their use is limited by adverse side effects. Luteolin is a flavonoid with anti-inflammatory actions that binds PPAR␥ but, unlike TZDs, does not promote adipocyte differentiation. However, previous reports suggested variously that luteolin is a PPAR␥ agonist or an antagonist. We show that luteolin exhibits weak partial agonist/ antagonist activity in transfections, inhibits several PPAR␥ target genes in 3T3-L1 cells (LPL, ORL1, and CEBP␣) and PPAR␥-dependent adipogenesis, but activates GLUT4 to a similar degree as rosiglitazone, implying gene-specific partial agonism. The crystal structure of the PPAR␥ ligand-binding domain (LBD) reveals that luteolin occupies a buried ligand-binding pocket (LBP) but binds an inactive PPAR␥ LBD conformer and occupies a space near the ␤-sheet region far from the activation helix (H12), consistent with partial agonist/antagonist actions. A single myristic acid molecule simultaneously binds the LBP, suggesting that luteolin may cooperate with other ligands to bind PPAR␥, and molecular dynamics simulations show that luteolin and myristic acid cooperate to stabilize the ⍀-loop among H2Ј, H3, and the ␤-sheet region. It is noteworthy that luteolin strongly suppresses hypertonicity-induced release of the pro-inflammatory interleukin-8 from human corneal epithelial cells and reverses reductions in transepithelial electrical resistance. This effect is PPAR␥-dependent. We propose that activities of luteolin are related to its singular binding mode, that anti-inflammatory activity does not require H12 stabilization, and that our structure can be useful in developing safe selective PPAR␥ modulators.

Identification of the Flavonoid Luteolin as a Repressor of the Transcription Factor Hepatocyte Nuclear Factor 4α

“…Structural studies have revealed that luteolin along with myristic acid occupies a ligand-binding pocket of PPAR␥ (35). The binding pocket occupied by luteolin is identical to that of the synthetic ligands thiazolidinediones, although each binding mode of PPAR␥ differs (35).…”

“…Structural studies have revealed that luteolin along with myristic acid occupies a ligand-binding pocket of PPAR␥ (35). The binding pocket occupied by luteolin is identical to that of the synthetic ligands thiazolidinediones, although each binding mode of PPAR␥ differs (35). The x-ray crystal structure studies using purified recombinant HNF4␣ protein revealed that the ligand-binding pocket of HNF4␣ contains a mixture of fatty acids, including lauric, myristic, and palmitic acids (36).…”

Hesperetin glucuronides induce adipocyte differentiation via activation and expression of peroxisome proliferator-activated receptor-γ

“…23) From analysis of the crystal structure of the PPARγ LBD, luteolin (5,7,3′,4′-tetrahydroxyflavone) in these compounds occupies a buried ligand-binding pocket of PPARγ but binds an inactive PPARγ LBD conformer and occupies a space near the β-sheet region far from the activation helix. 24) On the basis of our results on the additive effects and noncompetitive reactions with a thiazolidinedione derivative, we presumed that H7-OG and H3′-OG did not bind to PPARγ in the same manner as thiazolidinedione derivatives.…”

Biological activity and mechanisms of therapeutic action of rosmarinic acid, luteolin and its sulphated derivatives

“…ЛТ обладает слабой активностью частичного агониста/антагониста, ингибирует некоторые гены-мишени РАППg и РАППg-зависимый адипогенез [5], но подобно розиглитазону активирует транспортер глюкозы GLUT4, что подразумевает ген-специфический частичный агонизм [6]. Считается, что ЛТ может быть полезным для разработки безопасных селективных модуляторов РАППg [5,6,18].…”