Liver X receptor activation increases hepatic fatty acid desaturation by the induction of SCD1 expression through an LXRα-SREBP1c-dependent mechanism.
BACKGROUND
Liver X receptors (LXRs) including LXRα and LXRβ are members of the nuclear hormone receptor superfamily of ligand activated transcription factors, which serve as lipid sensors to regulate expression of genes controlling many aspects of cholesterol and fatty acid metabolism. The liver is the central organ in controlling lipid metabolism. In the present study, we aimed at elucidating the role of LXR activation in hepatic fatty acid homeostasis.


METHODS
We treated C57BL/6 mice with a synthetic non-selective LXR agonist TO901317. Fatty acid profile of lipid esters in the livers was analyzed by gas-liquid chromatography. Real-time polymerase chain reaction (PCR) and western blot were used to determine the expression of SREBP1c and SCD1 in TO901317-treated livers and HepG2 cells.


RESULTS
Oral administration of TO901317 resulted in increased fatty acid desaturation in the liver, with concomitant increase in hepatic stearoyl CoA desaturase-1 (SCD1) expression. TO901317-induced SCD1 expression was observed in LXRβ-/- mice, but not in LXRα-/- mice. Furthermore, TO901317 significantly increased expression of sterol regulatory element-binding protein 1c (SREBP1c), the deficiency of which almost completely abolished the induction of SCD1 by TO901317. This drug induced both SREBP1c and SCD1 expression in HepG2 cells. Overexpression of SREBP1c resulted in a significant increase in SCD1 promoter activity and expression.


CONCLUSIONS
Taken together, the present studies demonstrate that pan-LXR activation increases hepatic fatty acid desaturation via the induction of SCD1 expression in an LXRα-dependent and SREBP1c-mediated manner.
Department of Pediatrics, Peking University First Hospital, Beijing, China; Shenzhen University Diabetes Center, Shenzhen University Health Science Center, Shenzhen, China.
Xiaoyan
X
Zhang
Jia
J
Liu
Wen
W
Su
Jing
J
Wu
Chunjiong
C
Wang
Xiaomu
X
Kong
Jan-Åke
JÅ
Gustafsson
Jie
J
Ding
Xiaosong
X
Ma
Youfei
Y
Guan
D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D005227:Fatty Acids; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C497388:Srebf1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C490333:Scd1 protein, mouse
SCD1; SREBP1c; fatty acid desaturation; gene knockout mice; liver X receptor; 脂肪酸不饱和度，基因敲除小鼠，肝X受体，SCD1，SREBP1c