Activation of liver X receptor upregulates fatty acid synthase expression in diabetic kidney

Abstract

Objective To investigate the effect and mechanism of liver X receptor(LXR)agonist on expression of fatty acid synthase(FAS)in diabetic kidney. Methods In the part of in vivo study, immunostaining was used to detect the FAS protein expression in kidney. 16-week-old male db/db mice on C57BL/6 background were administered via gavage a LXR synthetic agonist, TO901317, at a dose of 3 mg·kg-1·d-1 or vehicle(0.5% Carboxymethyl Cellulose Sodium, CMC-Na)alone for 7 d; Quantitative RT-PCR and Western blot were used to detect mRNA and protein levels of FAS and SREBP-1. In the part of in vitro study, MCT cell(a mouse murine proximal tubule cell line)was treated with 10 μmol/L TO901317 for 24 h or transfected with active SREBP-1c expression vector(SREBP-1cN). HEK293 cells(a human renal tubule cell line)were transfected with mFAS-(1.7 kb)-luc, LXR expression vector or SREBP-1cN for 12 h. Quantitative RT-PCR and luciferase reproter assay were utilized to examine FAS mRNA level and FAS promoter activity. Results FAS was abundantly expressed in renal cortex, with low expresson in renal glomeruli. The mRNA and protein expressious of FAS in kidney of db/db mice were lowered compared with db/m mice. TO90137 treatment increased FAS mRNA expression by 1.3-fold. TO901317 increased expression of SREBP-1 in kidneys of db/m and db/db mice by 5.1-fold and 17-fold, respectively. TO901317 and overexpression of SREBP-1c increased expression of FAS in MCT cells by 1.5-fold and 1.8-fold. Transcription activity of FAS were induced by TO901317, LXR, and SREBP-1cN overexpressions in HEK293 cells. Conclusions Both direct(LXRE)and indirect(SREBP-1c)mechanisms may contribute to the up-regulation of FAS expression by LXR in renal proximal tubule cells. Key words: Liver X receptor; Sterol regulatory element-binding protein-1c; Fatty acid synthase; Diabetes mellitus, type 2