Matches in SemOpenAlex for { <https://semopenalex.org/work/W2807826933> ?p ?o ?g. }
Showing items 1 to 83 of
83
with 100 items per page.
- W2807826933 abstract "Liver X receptor (LXR) agonists increase plasma high density lipoprotein cholesterol (HDLc) rendering LXR an attractive drug target for anti-atherosclerotic therapies. However, LXR agonism simultaneously induces excessive hepatic triglyceride (TG) accumulation. This is currently a major drawback for the clinical application of LXR agonists. To obtain detailed insight into the underlying mechanisms, we employed a novel computational modeling approach called Analysis of Dynamic Adaptations in Parameter Trajectories (ADAPT). Our model predicted that both peripheral cholesterol efflux to HDL and hepatic HDLc uptake increase over time in LXR-agonist treated C57Bl6/J mice. A small imbalance in both fluxes leads to elevated plasma HDLc. Interestingly, and unexpectedly, the model also predicted that despite an increment in hepatic HDLc uptake, the affinity for HDLc decreased over time. This prediction was experimentally tested by analyzing scavenger receptor class B1 (SR-B1) protein expression in hepatic membranes. SR-B1 contributes to the hepatic uptake of cholesterol and SR-B1 levels were found to be decreased, confirming the model prediction. Analysis of TG fluxes furthermore showed that both input and output fluxes to hepatic TG content are strongly induced upon LXR activation, and that hepatic TG accumulation in the early phase of LXR agonist treatment results from only a minor imbalance between the two. It is generally believed that LXR-induced liver steatosis results from increased de novo lipogenesis (DNL). ADAPT, however, predicted that the hepatic influx of free fatty acids (FFA) is the major contributor to early hepatic TG accumulation upon LXR activation. Validation of this prediction indeed showed a 5-fold increase in FFA flux from plasma to hepatic monounsaturated fatty acids upon acute LXR activation, while DNL was not yet significantly increased at this time. This study illustrates that application of state of the art computational modeling produces unexpected predictions that are amenable to validation and leads to novel insights into the complex biological network that coordinates systemic lipid metabolism. Funded by EC (FP7 no. 305707 RESOLVE)." @default.
- W2807826933 created "2018-06-21" @default.
- W2807826933 creator A5024107234 @default.
- W2807826933 date "2015-02-10" @default.
- W2807826933 modified "2023-09-26" @default.
- W2807826933 title "A systems biology approach reveals the physiological origin of increased plasma HDL levels and hepatic steatosis induced by liver X receptor activation" @default.
- W2807826933 hasPublicationYear "2015" @default.
- W2807826933 type Work @default.
- W2807826933 sameAs 2807826933 @default.
- W2807826933 citedByCount "0" @default.
- W2807826933 crossrefType "journal-article" @default.
- W2807826933 hasAuthorship W2807826933A5024107234 @default.
- W2807826933 hasConcept C104317684 @default.
- W2807826933 hasConcept C110459506 @default.
- W2807826933 hasConcept C126322002 @default.
- W2807826933 hasConcept C134018914 @default.
- W2807826933 hasConcept C141359234 @default.
- W2807826933 hasConcept C167400880 @default.
- W2807826933 hasConcept C170493617 @default.
- W2807826933 hasConcept C185592680 @default.
- W2807826933 hasConcept C2776175330 @default.
- W2807826933 hasConcept C2778163477 @default.
- W2807826933 hasConcept C2778772119 @default.
- W2807826933 hasConcept C2778913445 @default.
- W2807826933 hasConcept C2778938600 @default.
- W2807826933 hasConcept C2779134260 @default.
- W2807826933 hasConcept C2780072125 @default.
- W2807826933 hasConcept C41443022 @default.
- W2807826933 hasConcept C4733338 @default.
- W2807826933 hasConcept C55493867 @default.
- W2807826933 hasConcept C63932345 @default.
- W2807826933 hasConcept C71924100 @default.
- W2807826933 hasConcept C86339819 @default.
- W2807826933 hasConcept C86803240 @default.
- W2807826933 hasConceptScore W2807826933C104317684 @default.
- W2807826933 hasConceptScore W2807826933C110459506 @default.
- W2807826933 hasConceptScore W2807826933C126322002 @default.
- W2807826933 hasConceptScore W2807826933C134018914 @default.
- W2807826933 hasConceptScore W2807826933C141359234 @default.
- W2807826933 hasConceptScore W2807826933C167400880 @default.
- W2807826933 hasConceptScore W2807826933C170493617 @default.
- W2807826933 hasConceptScore W2807826933C185592680 @default.
- W2807826933 hasConceptScore W2807826933C2776175330 @default.
- W2807826933 hasConceptScore W2807826933C2778163477 @default.
- W2807826933 hasConceptScore W2807826933C2778772119 @default.
- W2807826933 hasConceptScore W2807826933C2778913445 @default.
- W2807826933 hasConceptScore W2807826933C2778938600 @default.
- W2807826933 hasConceptScore W2807826933C2779134260 @default.
- W2807826933 hasConceptScore W2807826933C2780072125 @default.
- W2807826933 hasConceptScore W2807826933C41443022 @default.
- W2807826933 hasConceptScore W2807826933C4733338 @default.
- W2807826933 hasConceptScore W2807826933C55493867 @default.
- W2807826933 hasConceptScore W2807826933C63932345 @default.
- W2807826933 hasConceptScore W2807826933C71924100 @default.
- W2807826933 hasConceptScore W2807826933C86339819 @default.
- W2807826933 hasConceptScore W2807826933C86803240 @default.
- W2807826933 hasLocation W28078269331 @default.
- W2807826933 hasOpenAccess W2807826933 @default.
- W2807826933 hasPrimaryLocation W28078269331 @default.
- W2807826933 hasRelatedWork W1967492342 @default.
- W2807826933 hasRelatedWork W1977835632 @default.
- W2807826933 hasRelatedWork W2001079924 @default.
- W2807826933 hasRelatedWork W2022493303 @default.
- W2807826933 hasRelatedWork W2050294137 @default.
- W2807826933 hasRelatedWork W2077189160 @default.
- W2807826933 hasRelatedWork W2092789730 @default.
- W2807826933 hasRelatedWork W2106169706 @default.
- W2807826933 hasRelatedWork W2110527632 @default.
- W2807826933 hasRelatedWork W2134645520 @default.
- W2807826933 hasRelatedWork W2137188051 @default.
- W2807826933 hasRelatedWork W2141256126 @default.
- W2807826933 hasRelatedWork W2142423308 @default.
- W2807826933 hasRelatedWork W2147321151 @default.
- W2807826933 hasRelatedWork W2588914123 @default.
- W2807826933 hasRelatedWork W2604462366 @default.
- W2807826933 hasRelatedWork W2883883463 @default.
- W2807826933 hasRelatedWork W3092631461 @default.
- W2807826933 hasRelatedWork W3175648652 @default.
- W2807826933 hasRelatedWork W88954364 @default.
- W2807826933 isParatext "false" @default.
- W2807826933 isRetracted "false" @default.
- W2807826933 magId "2807826933" @default.
- W2807826933 workType "article" @default.