Angiopoietin-like Protein 3 Mediates Hypertriglyceridemia Induced by the Liver X Receptor

Abstract

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 angiopoietinlike protein 3 (Angptl3), a liver-specific secretory protein, which had suppressive effect on lipoprotein lipase activity. In the current study, LXR ligands augmented Angptl3 mRNA expression and protein production in hepatoma cells. LXR ligands and LXR⅐retinoid X receptor (RXR) complex increased the promoter activity of Angptl3 gene. Serial deletion and point mutation of Angptl3 promoter identified an LXR response element (LXRE). Gel mobility shift assay showed the direct binding of LXR⅐RXR complex to the LXRE of the Angptl3 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 Angptl3. In Angptl3-deficient C57BL/6J mice, LXR ligand did not cause hypertriglyceridemia but accumulation of triglyceride in the liver. Our results demonstrate that Angptl3 is a direct target of LXR and that induction of hepatic Angptl3 accounts for hypertriglyceridemia associated with the treatment of LXR ligand.

Nuclear Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors

“…LXRs regulate expression of SREBP-1c, a transcription factor that enhances the expression of genes involved in fatty acid biosynthesis (20). LXRs also activate fatty acid synthase and angiopoietin-like protein 3, a liver-specific secretory protein that inactivates lipoprotein lipase and increases plasma triglyceride levels (20,31). Because LXRs have both antiatherogenic and lipogenic activities, the development of LXR agonists that regulate cholesterol metabolism without causing hypertriglycemia is of great pharmacological interest.…”

GPIHBP1, a GPI-anchored protein required for the lipolytic processing of triglyceride-rich lipoproteins

“…Along the way, several "supporting actors" (e.g., apo-CIII, apo-AV, ANGPTL3, ANGPTL4) have appeared (5)(6)(7)(8). These molecules regulate the efficiency of lipolysis, and deficiencies in these proteins perturb plasma triglyceride levels.…”

Liver X Receptor: A Cardinal Target for Atherosclerosis and Beyond

“…Severe hepatic steatosis develops in mice upon LXR agonist treatment; many studies have explained this effect based on the direct upregulation of SREBP1c, the major SREBP1 isoform, in the liver, which stimulates the transcription of lipogenic genes, such as fatty acid synthase [FAS], acetyl-coA carboxylase [ACC] and stearoyl-coenzyme A desaturase 1 [SCD1], a rate-limiting enzyme necessary for the biosynthesis of monounsaturated acids 63,64) . In one study, it was found that angiopoietin-like protein 3 [Angptl3] 65) , a liver-secreted protein that increases the plasma triglyceride level by inhibiting the LPL activity in different tissues and the free fatty acid levels by activating lipolysis in adipocytes, exhibits an increased expression, while apoA-V is downregulated, following LXR activation 66) .…”