Rescue of Neurons from Ischemic Injury by Peroxisome Proliferator-Activated Receptor-γ Requires a Novel Essential Cofactor LMO4

Activation of peroxisome proliferator-activated receptor-gamma (PPAR gamma) signaling after stroke may reduce brain injury, but this effect will depend on the levels of receptor and cofactors. Here, we showed that the direct effect of PPAR gamma signaling to protect neurons from ischemic injury requires a novel cofactor LMO4, because this effect was lost in LMO4-null cortical neurons. PPAR gamma agonist also failed to reduce cerebral infarction after transient focal ischemia in CaMKII alpha Cre/LMO4loxP mice with LMO4 ablated in neurons of the forebrain. Expressing LMO4 in LMO4-null cortical neurons rescued the PPAR gamma-protective effect. PPAR gamma signaling activates the promoter of the antioxidant gene SOD2 and this process requires LMO4. Addition of a superoxide dismutase mimetic MnTBAP [ manganese(III) tetrakis(4-benzoic acid)porphyrin] bypassed the deficiency in PPAR gamma signaling and was able to directly rescue LMO4-null cortical neurons from ischemic injury. Like LMO4, PPAR gamma and PGC1 alpha(PPAR gamma coactivator 1 alpha) levels in neurons are elevated by hypoxic stress, and absence of LMO4 impairs their upregulation. Coimmunoprecipitation and mammalian two-hybrid assays revealed thatLMO4interacts in a ligand-dependent manner with PPAR gamma. LMO4augments PPAR gamma-dependent gene activation, in part, by promoting RXR alpha (retinoid X receptor-alpha) binding to PPAR gamma and by increasing PPAR gamma binding to its target DNA sequence. Together, our results identify LMO4 as an essential hypoxia-inducible cofactor required for PPAR gamma signaling in neurons. Thus, upregulation of LMO4 expression after stroke is likely to be an important determinant of neuron survival.