Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles.
The oxysterol-activated liver X receptor (LXR) provides a link between sterol and fatty acid metabolism; activation of LXR induces transcription of lipogenic genes. This study shows that induction of the lipogenic genes Srebp-1c, Fas, and Acc1 upon administration of the synthetic LXR agonist T0901317 to C57BL/6J mice (10 mg/kg/day, 4 days) is associated with massive hepatic steatosis along the entire liver lobule and a 2.5-fold increase in very low density lipoprotein-triglyceride (VLDL-TG) secretion. The increased VLDL-TG secretion was fully accounted for by formation of larger (129 +/- 9 nm versus 94 +/- 12 nm, a 2.5-fold increase of particle volume) TG-rich particles. Stimulation of VLDL-TG secretion did not lead to elevated plasma TG levels in C57BL/6J mice, indicating efficient particle metabolism and clearance. However, T0901317 treatment did lead to severe hypertriglyceridemia in mouse models of defective TG-rich lipoprotein clearance, i.e. APOE*3-Leiden transgenic mice (3.2-fold increase) and apoE-/- LDLr-/- double knockouts (12-fold increase). Incubation of rat hepatoma McA-RH7777 cells with T0901317 also resulted in intracellular TG accumulation and enhanced TG secretion. We conclude that, in addition to raising high density lipoprotein cholesterol concentrations, pharmacological LXR activation in mice leads to development of hepatic steatosis and secretion of atherogenic, large TG-rich VLDL particles.
Grefhorst
Aldo
A
Laboratory of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University Hospital Groningen, Hanzeplein 1, 9713 RB Groningen, The Netherlands.
Elzinga
Baukje M
BM
Voshol
Peter J
PJ
Plösch
Torsten
T
Kok
Tineke
T
Bloks
Vincent W
VW
van der Sluijs
Fjodor H
FH
Havekes
Louis M
LM
Romijn
Johannes A
JA
Verkade
Henkjan J
HJ
Kuipers
Folkert
F
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D015228:Hypertriglyceridemia / Q000209:etiology; D008055:Lipids / Q000096:biosynthesis*; D008079:Lipoproteins, VLDL / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D013449:Sulfonamides; D014280:Triglycerides / Q000096:biosynthesis*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008055:Lipids; D008079:Lipoproteins, VLDL; D000071518:Liver X Receptors; D008565:Membrane Proteins; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D013449:Sulfonamides; D014280:Triglycerides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C030106:very low density lipoprotein triglyceride