Premium
Liver X receptor (LXR) agonist TO‐901317 restores renal fatty acid synthase (FAS) expression in db/db mice
Author(s) -
Guan Tiao,
Wang Bing,
Zhang Yahua,
Breyer Matthew,
Guan Youfei
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a840-d
Kidney plays an important role in lipid homeostasis. Aberrant renal lipid metabolism has been shown to accelerate diabetic nephropathy. Since LXRs are intracellular sterol sensors controlling fatty acid and cholesterol metabolism, we investigated the effect of a selective LXR agonist TO‐901317 on renal FAS gene expression in db/db mouse, a murine model of type 2 diabetes. Immunostaining revealed that FAS was abundantly located in the proximal tubules, where LXRs were also highly expressed. Renal FAS expression of db/db mice was significantly reduced compared to non‐diabetic db/m control mice. Treatment of db/db mice with TO‐901317 (3 mg.kg(−1).day(−1)) for 7 days markedly restored FAS expression. To further explore the mechanism by which TO‐901317 enhances renal FAS expression, MCT cell, a murine proximal tubule cell line, was utilized. Endogenous LXR activity was evident in MCT cells and TO‐901317 (10 μM) treatment for 24 hours resulted in significant increase in FAS mRNA expression. Furthermore, LXR activation also led to marked induction of SREBP‐1, a well‐documented LXR target gene and a critical transcription factor involved in fatty acid metabolism. Promoter analysis of FAS gene revealed several putative LXRE and SRE sites. Overexpression of an active form of SREBP‐1c (SREBP‐1cN) and treatment with TO‐901317 resulted in marked increase in FAS gene transcription (p<0.01). Taken together, LXR activation restored FAS expression likely via both direct (LXRE) and indirect (SREBP‐1) mechanisms in db/db mice. LXR activator may be a useful agent for treating lipid‐related renal injury in type 2 diabetes.