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Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Grefhorst, Aldo Elzinga, Baukje M. Voshol, Peter Jacobus Plösch, Torsten Kok, Tineke Bloks, Vincent W. Sluijs, Fjodor H. Van Der Havekes, Louis M. Romijn, Johannes Anthonius Verkade, Henkjan J. Kuipers, Folkert |
| Copyright 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. |
| Starting Page | 465 |
| Ending Page | 473 |
| Page Count | 9 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://www.rug.nl/research/portal/files/2879850/c3.pdf |
| Alternate Webpage(s) | https://www.rug.nl/research/portal/files/38531389/34182.full.pdf |
| PubMed reference number | 12097330v1 |
| Volume Number | 277 |
| Issue Number | 37 |
| Journal | The Journal of biological chemistry |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acetyl-CoA Carboxylase 1 Fatty Acids Fatty degeneration Fatty-acid synthase High Density Lipoprotein Cholesterol Hypertriglyceridemia Kidney Diseases LDLR protein, human Large Liver X Receptor-Like Family Liver X Receptors Liver diseases Lobule Low-Density Lipoproteins Milligram per Kilogram per Day Oxysterols Pharmacology Steatohepatitis TO-901317 Triglycerides Very low density lipoprotein fatty acid metabolism mg/kg |
| Content Type | Text |
| Resource Type | Article |
