Abstract 13152: A Novel Link between Energy Expenditure, Plasma Lipid Turnover, and Cardiovascular Health
| Autor: | Pirkka-Pekka Laurila, Jarkko Soronen, Mariëtte Boon, Marja-Riitta Taskinen, Samuli Ripatti, Patrick Rensen, Petri Kovanen, Matti Jauhiainen |
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| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | Circulation. 130 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | We previously showed that USF1 transcription factor was associated with familial combined hyperlipidemia in Finns. In the current study, we have conducted a detailed metabolic characterization of Usf1 in mice. We generated a congenic strain of Usf1 knockout mice, fed with high-fat diet for 5 months. The knockouts displayed both elevated cholesterol and phospholipids in their plasma HDL-fractions and lower total and VLDL-triglycerides. This was due to both enhanced TRL clearance linked to elevated LPL activity of the knockouts, and reduced hepatic VLDL secretion. The elevated HDL-C levels were associated with increased efflux capacity of HDL particles derived from Usf1-/- mice. The detailed analysis of Usf1-/- HDL composition revealed an enrichment of phospholipids, known to enhance the efflux capacity of HDL particles. The Usf1-/- mice were protected against HFD induced obesity despite being physically less active and eating more than Usf1+/+ mice. Furthermore, they were protected against insulin resistance, atherosclerosis, and fatty liver. Multiplex measurements revealed a reduction in the cytokines representing vascular inflammation. While absorption of lipids was similar between Usf1-/- and Usf1+/+ mice, the Usf1-/- mice displayed elevated VO2 and VCO2, even in thermoneutral conditions, suggesting an increased metabolic rate. Analysis of post-injection organ distribution of [3H]triolein and [14C] cholesteryl oleate revealed a selective uptake of TRLs to brown adipose tissue in Usf1-/- mice, mediated by an LPL-dependent mechanism, as inhibiting LPL by tetrahydrolipstatin completely eliminated lipoprotein uptake to BAT. There was a dramatic 8-fold reduction in lipid droplet size as well as lipid content of BAT. The protein levels of mitochondrial complex II were elevated in the BAT of Usf1-/- mice. Furthermore, PET/CT measurements demonstrated an increased glucose uptake to BAT of Usf1-/- mice. Together, these findings demonstrate overall avidity of BAT to process energy substrates. Our data establish the critical role of Usf1 as a metabolic master-regulator, and demonstrate that Usf1 deficiency leads to a remarkably beneficial metabolic profile in mice. Our discoveries make USF1 appear a particularly attractive therapeutic target. |
| Databáze: | OpenAIRE |
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