Liver X receptor α induces 17ß-hydroxysteroid dehydrogenase-13 expression through SREBP-1c.

ABSTRACT

Liver X receptors, including LXRα and LXRß, are known to be master regulators of liver lipid metabolism. Activation of LXRα increases hepatic lipid storage in lipid droplets (LDs). 17ß-Hydroxysteroid dehydrogenase-13 (17ß-HSD13), a recently identified liver-specific LD-associated protein, has been reported to be involved in the development of nonalcoholic fatty liver disease. However, little is known about its transcriptional regulation. In the present study, we aimed at determining whether 17ß-HSD13 gene transcription is controlled by LXRs. We found that treatment with T0901317, a nonspecific LXR agonist, increased both 17ß-HSD13 mRNA and protein levels in cultured hepatocytes. It also significantly upregulated hepatic 17ß-HSD13 expression in wild-type (WT) and LXRß-/- mice but not in LXRα-/- mice. Basal expression of 17ß-HSD13 in the livers of LXRα-/- mice was lower than that in the livers of WT and LXRß-/- mice. Moreover, induction of hepatic 17ß-HSD13 expression by T0901317 was almost completely abolished in SREBP-1c-/- mice. Bioinformatics analysis revealed a consensus sterol regulatory element (SRE)-binding site in the promoter region of the 17ß-HSD13 gene. A 17ß-HSD13 gene promoter-driven luciferase reporter and ChIP assays further confirmed that the 17ß-HSD13 gene was under direct control of SREBP-1c. Collectively, these findings demonstrate that LXRα activation induces 17ß-HSD13 expression in a SREBP-1c-dependent manner. 17ß-HSD13 may be involved in the development of LXRα-mediated fatty liver.