Liver X receptors (LXRs) suppress the expression of inflammatory genes in a context-specific manner. In astrocytes, SUMOylation of LXRs promotes their anti-inflammatory effects. We found that small heterodimer partner (SHP), also known as NR0B2 (nuclear receptor subfamily 0, group B, member 2), facilitates the anti-inflammatory actions of LXRs by promoting their SUMOylation. Knockdown of SHP abrogated SUMOylation of LXRs, preventing their anti-inflammatory effects, in primary rat astrocytes but not macrophages. The underlying mechanisms differed according to LXR isoform. SHP promoted SUMO2 and SUMO3 attachment to LXRα by interacting directly with the histone deacetylase and E3 SUMO ligase HDAC4. In contrast, SHP promoted SUMO1 attachment to LXRβ by stabilizing the E3 SUMO ligase PIAS1. SHP bound PIAS1 and disrupted its interaction with the E3 ubiquitin ligase SIAH1. Knocking down SIAH1 rescued LXRβ SUMOylation in SHP-deficient astrocytes. Our data collectively suggested that SHP mediates the anti-inflammatory actions of LXRs through differential regulation of receptor SUMOylation specifically in astrocytes, thereby revealing potential avenues for therapeutic development in diseases associated with brain inflammation.