Role of LXRs in control of lipogenesis.
The discovery of oxysterols as the endogenous liver X receptor (LXR) ligands and subsequent gene targeting studies in mice provided strong evidence that LXR plays a central role in cholesterol metabolism. The identification here of a synthetic, nonsteroidal LXR-selective agonist series represented by T0314407 and T0901317 revealed a novel physiological role of LXR. Oral administration of T0901317 to mice and hamsters showed that LXR activated the coordinate expression of major fatty acid biosynthetic genes (lipogenesis) and increased plasma triglyceride and phospholipid levels in both species. Complementary studies in cell culture and animals suggested that the increase in plasma lipids occurs via LXR-mediated induction of the sterol regulatory element-binding protein 1 (SREBP-1) lipogenic program.
Schultz
J R
JR
Tularik Inc., South San Francisco, California 94080, USA.
Tu
H
H
Luk
A
A
Repa
J J
JJ
Medina
J C
JC
Li
L
L
Schwendner
S
S
Wang
S
S
Thoolen
M
M
Mangelsdorf
D J
DJ
Lustig
K D
KD
Shan
B
B
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000096:biosynthesis; D015228:Hypertriglyceridemia / Q000209:etiology; D008055:Lipids / Q000096:biosynthesis*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008817:Mice, Mutant Strains; D057093:Orphan Nuclear Receptors; D010743:Phospholipids / Q000097:blood; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides / Q000494:pharmacology*; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D008055:Lipids; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C417043:T 0314407; D014157:Transcription Factors; D014280:Triglycerides