Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by the liver X receptor

The KK/ San obese and diabetic mouse, a mutant strain from KK obese mice, exhibits significantly low plasma triglyceride levels. In KK/ San mice, genetic analysis identified a mutation in the gene encoding angiopoietin-like protein 3 ( Angpt13), a liver- specific secretory protein, which had suppressive effect on lipoprotein lipase activity. In the current study, LXR ligands augmented Angpt13 mRNA expression and protein production in hepatoma cells. LXR ligands and LXR . retinoid X receptor ( RXR) complex increased the promoter activity of Angpt13 gene. Serial deletion and point mutation of Angpt13 promoter identified an LXR response element ( LXRE). Gel mobility shift assay showed the direct binding of LXR . RXR complex to the LXRE of the Angpt13 promoter. Furthermore, treatment of mice with synthetic LXR ligand caused triglyceride accumulation in the liver and plasma, which was accompanied by induction of hepatic mRNAs of several LXR target genes, including sterol regulatory element binding protein- 1c ( SREBP- 1c), fatty acid synthase ( FAS), and Angpt13. In Angpt13- deficient C57BL/ 6J mice, LXR ligand did not cause hypertriglyceridemia but accumulation of triglyceride in the liver. Our results demonstrate that Angpt13 is a direct target of LXR and that induction of hepatic Angpt13 accounts for hypertriglyceridemia associated with the treatment of LXR ligand.