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June 1, 2003Journal of Biological ChemistryOpen Access

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

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Population

Hepatoma cells, KK/San obese and diabetic mice, and Angptl3-deficient C57BL/6J mice

Comparison

Synthetic LXR ligand vs Untreated control (implied)

Design

Preclinical

Authors

TIToshimori InabaDaiichi Sankyo (Germany)MMMorihiro MatsudaKawasaki HospitalMSMitsuru ShimamuraTokyo Institute of Technology

Discussion

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Implication

Angptl3 mediates LXR-induced hypertriglyceridemia in mice; hypothesis-generating for Angptl3-targeted therapies in humans.

Key Points

  • To determine whether angiopoietin-like protein 3 (Angptl3) is a direct transcriptional target of the liver X receptor (LXR) and mediates LXR-induced hypertriglyceridemia.
  • Assessed Angptl3 mRNA expression, promoter activity, and LXR-RXR complex binding in hepatoma cells using deletion, point mutation, and gel mobility shift assays.
  • Treated wild-type and Angptl3-deficient C57BL/6J mice with a synthetic LXR ligand to examine hepatic target gene expression and triglyceride accumulation in liver and plasma.
  • LXR ligands and the LXR-RXR complex directly bound a newly identified LXR response element (LXRE) in the Angptl3 promoter, increasing promoter activity and Angptl3 production.
  • Synthetic LXR ligand treatment induced hepatic SREBP-1c, FAS, and Angptl3 expression, triggering both hepatic and plasma triglyceride accumulation in wild-type mice.
  • Angptl3-deficient C57BL/6J mice treated with LXR ligand accumulated triglycerides in the liver but completely failed to develop hypertriglyceridemia.

Structured PICO

P
Population
Hepatoma cells, KK/San obese and diabetic mice, and Angptl3-deficient C57BL/6J mice
I
Intervention
Synthetic LXR ligand
C
Comparator
Untreated control (implied)
O
Outcome
Triglyceride accumulation in liver and plasma, and Angptl3 expressionsurrogate

Angptl3 is a direct target of LXR, and its hepatic induction accounts for LXR ligand-associated hypertriglyceridemia.

Cite This Study

Inaba et al. (2003) studied this question.

synapsesocial.com/papers/6a80835ecf96de1eb9c88099https://doi.org/10.1074/jbc.m213202200
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Also Consider

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  1. 1LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes2001 · 675 citations
  2. 2ANGPTL3 Stimulates Endothelial Cell Adhesion and Migration via Integrin αvβ3 and Induces Blood Vessel Formation in Vivo2002 · 256 citations
  3. 3Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors.1995 · 364 citations
  4. 4Insulin resistance and cardiovascular disease2000 · 1,392 citations
  5. 5Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors.1994 · 256 citations