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 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 LXR.retinoid 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 LXR.RXR 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.
Inaba
Toshimori
T
Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Matsuda
Morihiro
M
Shimamura
Mitsuru
M
Takei
Norihide
N
Terasaka
Naoki
N
Ando
Yosuke
Y
Yasumo
Hiroaki
H
Koishi
Ryuta
R
Makishima
Makoto
M
Shimomura
Iichiro
I
D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D064429:Fatty Acid Synthases / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D015228:Hypertriglyceridemia / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D008024:Ligands; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009154:Mutation; D057093:Orphan Nuclear Receptors; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D013449:Sulfonamides; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D014407:Tumor Cells, Cultured; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D064429:Fatty Acid Synthases; D006845:Hydrocarbons, Fluorinated; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012313:RNA; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013449:Sulfonamides; D014157:Transcription Factors; D014280:Triglycerides; C404495:Angptl3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides