Liver <scp>X</scp> receptor activation increases hepatic fatty acid desaturation by the induction of <scp>SCD1</scp> expression through an <scp>LXR</scp>α‐<scp>SREBP1c</scp>‐dependent mechanism (肝X受体活化可通过LXRα‐SREBP1c依赖的机制诱导SCD1表达来增加肝脏脂肪酸不饱和度)

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Liver <jats:styled-content style="fixed-case">X</jats:styled-content> receptors (<jats:styled-content style="fixed-case">LXRs</jats:styled-content>) including <jats:styled-content style="fixed-case">LXR</jats:styled-content>α and <jats:styled-content style="fixed-case">LXR</jats:styled-content>β 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 <jats:styled-content style="fixed-case">LXR</jats:styled-content> activation in hepatic fatty acid homeostasis.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We treated <jats:styled-content style="fixed-case">C57BL</jats:styled-content>/6 mice with a synthetic non‐selective <jats:styled-content style="fixed-case">LXR</jats:styled-content> agonist <jats:styled-content style="fixed-case">TO901317</jats:styled-content>. Fatty acid profile of lipid esters in the livers was analyzed by gas‐liquid chromatography. Real‐time polymerase chain reaction (<jats:styled-content style="fixed-case">PCR</jats:styled-content>) and western blot were used to determine the expression of <jats:styled-content style="fixed-case">SREBP1c</jats:styled-content> and <jats:styled-content style="fixed-case">SCD1</jats:styled-content> in <jats:styled-content style="fixed-case">TO901317</jats:styled-content>‐treated livers and <jats:styled-content style="fixed-case">HepG2</jats:styled-content> cells.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Oral administration of <jats:styled-content style="fixed-case">TO901317</jats:styled-content> resulted in increased fatty acid desaturation in the liver, with concomitant increase in hepatic stearoyl <jats:styled-content style="fixed-case">CoA</jats:styled-content> desaturase‐1 (<jats:styled-content style="fixed-case">SCD1</jats:styled-content>) expression. <jats:styled-content style="fixed-case">TO901317</jats:styled-content>‐induced <jats:styled-content style="fixed-case">SCD1</jats:styled-content> expression was observed in <jats:styled-content style="fixed-case">LXR</jats:styled-content>β<jats:styled-content style="fixed-case">‐/‐</jats:styled-content> mice, but not in <jats:styled-content style="fixed-case">LXR</jats:styled-content>α‐/‐ mice. Furthermore, <jats:styled-content style="fixed-case">TO901317</jats:styled-content> significantly increased expression of sterol regulatory element‐binding protein 1c (<jats:styled-content style="fixed-case">SREBP1c</jats:styled-content>), the deficiency of which almost completely abolished the induction of <jats:styled-content style="fixed-case">SCD1</jats:styled-content> by <jats:styled-content style="fixed-case">TO901317</jats:styled-content>. This drug induced both <jats:styled-content style="fixed-case">SREBP1c</jats:styled-content> and <jats:styled-content style="fixed-case">SCD1</jats:styled-content> expression in <jats:styled-content style="fixed-case">HepG2</jats:styled-content> cells. Overexpression of <jats:styled-content style="fixed-case">SREBP1c</jats:styled-content> resulted in a significant increase in <jats:styled-content style="fixed-case">SCD1</jats:styled-content> promoter activity and expression.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Taken together, the present studies demonstrate that pan‐<jats:styled-content style="fixed-case">LXR</jats:styled-content> activation increases hepatic fatty acid desaturation via the induction of <jats:styled-content style="fixed-case">SCD1</jats:styled-content> expression in an <jats:styled-content style="fixed-case">LXR</jats:styled-content>α‐dependent and <jats:styled-content style="fixed-case">SREBP1c</jats:styled-content>‐mediated manner.</jats:p></jats:sec>