A Functional Cross-Talk between Liver X Receptor-α and Constitutive Androstane Receptor Links Lipogenesis and Xenobiotic Responses

Abstract

The liver X receptor (LXR) and constitutive androstane receptor (CAR) are two nuclear receptors postulated to have distinct functions. LXR is a sterol sensor that promotes lipogenesis, whereas CAR is a xenosensor that controls xenobiotic responses. Here, we show that LXR␣ and CAR are functionally related in vivo. Loss of CAR increased the expression of lipogenic LXR target genes, leading to increased hepatic triglyceride accumulation, whereas activation of CAR inhibited the expression of LXR target genes and LXR ligand-induced lipogenesis. On the other hand, a combined loss of LXR ␣ and ␤ increased the basal expression of xenobiotic CAR target genes, whereas activation of LXR inhibited the expression of CAR target genes and sensitized mice to xenobiotic toxicants. The mutual suppression between LXR␣ and CAR was also observed in cell culture and reporter gene assays. LXR␣, like CAR, exhibited constitutive activity in the absence of an exogenously added ligand by recruiting nuclear receptor coactivators. Interestingly, although CAR competed with LXR␣ for coactivators, the constitutive activity and recruitment of coactivators was not required for CAR to suppress the activity of LXR␣. In vivo chromatin immunoprecipitation assay showed that cotreatment of a CAR agonist compromised the LXR agonist responsive recruitment of LXR␣ to Srebp-1c, whereas an LXR agonist inhibited the CAR agonist-responsive recruitment of CAR to Cyp2b10. In conclusion, our results have revealed dual functions of LXR␣ and CAR in lipogenesis and xenobiotic responses, establishing a unique role of these two receptors in integrating xenobiotic and endobiotic homeostasis.

Pregnane X Receptor and Constitutive Androstane Receptor at the Crossroads of Drug Metabolism and Energy Metabolism

“…In contrast, a combined loss of LXR ␣ and ␤ increased the basal expression of xenobiotic CAR target genes; whereas activation of LXR inhibited the expression of CAR target genes and sensitized mice to xenobiotic toxicants. The mutual suppression between LXR␣ and CAR was also observed in cell culture and reporter gene assays (Zhai et al, 2010).…”

“…In one study, it was suggested that activation of CAR or PXR reduced the level of SREBP-1 by inducing Insig-1, a protein blocking the proteolytic activation of SREBPs (Roth et al, 2008b). Our own study suggested that CAR may inhibit lipogenesis by inhibiting the LXR agonist responsive recruitment of LXR␣ to the Srebp-1c gene promoter (Zhai et al, 2010).…”

“…Mechanistically, it has been shown that PXR can directly interact with Forkhead box A2 (FoxA2) and prevent FoxA2 binding to the Cpt1a and Hmgcs2 gene promoters (Nakamura et al, 2007). Finally, unlike CAR, activation of PXR had little effect on the lipogenic effect of LXR (Zhai et al, 2010).…”

Deciphering the roles of the constitutive androstane receptor in energy metabolism

“…Crosstalk between CAR and LXR causes mutual repression through coactivator-binding competition. Consequently, the expression of LXR target genes are down-regulated, including lipogenic genes, such as Srebp1, Acc1, Fas, and Scd1 [75] . CAR also directly binds to SREBP1, which suggests potential crosstalk between CAR and SREBP1 in the context of lipogenesis, although further functional and mechanistic studies are needed to prove this association [76] .…”

“…However, several CAR inhibitory factors, such as sterol regulatory elementbinding protein 1 (SREBP1), liver X receptor (LXR), farnesoid X receptor (FXR), estrogen receptor (ER), and histone deacetylase 1 (HDAC1), also exist [72][73][74][75][76] . The inhibitory crosstalk attenuates CAR activity and down-regulates drug-metabolizing enzymes.…”