Abstract 13152: A Novel Link between Energy Expenditure, Plasma Lipid Turnover, and Cardiovascular Health
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.
Author Disclosures: P. Laurila: None. J. Soronen: None. M. Boon: None. M. Taskinen: None. S. Ripatti: None. P. Rensen: None. P. Kovanen: None. M. Jauhiainen: None.
- © 2014 by American Heart Association, Inc.