Title
Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles
Author
Gaubius Instituut TNO
Grefhorst, A.
Elzinga, B.M.
Voshol, P.J.
Plösch, T.
Kok, T.
Bloks, V.W.
van der Sluijs, F.H.
Havekes, L.M.
Romijn, J.A.
Verkade, H.J.
Kuipers, F.
Publication year
2002
Abstract
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. Chemicals/CAS: Anticholesteremic Agents; Apolipoproteins E; Carrier Proteins; DNA-Binding Proteins; Lipids; Lipoproteins, VLDL; liver X receptor; Membrane Proteins; Phospholipid Transfer Proteins; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; Sulfonamides; T 0901317; Triglycerides; very low density lipoprotein triglyceride
Subject
Animals
Anticholesteremic Agents
Apolipoproteins E
Carrier Proteins
Cell Line
DNA-Binding Proteins
Hypertriglyceridemia
Lipids
Lipoproteins, VLDL
Liver
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Phospholipid Transfer Proteins
Rats
Receptors, Cytoplasmic and Nuclear
Receptors, LDL
Receptors, Retinoic Acid
Receptors, Thyroid Hormone
Sulfonamides
Triglycerides
Animalia
Mus musculus
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DOI
https://doi.org/10.1074/jbc.m204887200
TNO identifier
236689
ISSN
0021-9258
Source
Journal of Biological Chemistry, 277 (277), 34182-34190
Document type
article