Liver X Receptors : expression and functions in human placenta
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Abstract
Liver X Receptor og genregulering i morkaken (placenta).Cand. Scient. Susanne Weedon-Fekjær har i sin doktorgrad studert rollene til transkripsjonsfaktorene Liver X Receptors (LXR) i morkake og morkakeceller hos friske gravide og gravide med svangerskapsforgiftning (preeklampsi).
Morkaken er nødvendig for transport av næringsstoffer til fosteret under svangerskapet. Morkaken antas også å spille en viktig rolle i utviklingen av svangerskapsforgiftning, en sykdom som rammer ca. 3.5% av alle norske gravide. Metabolisme og transport av fettsyrer over morkaken er viktig for vekst og utvikling av fosteret. Ved svangerskapsforgiftning kan man se forhøyete verdier av fettstoffer i mors blod.
I sin avhandling "Liver X Receptors – expression and functions in human placenta" har Weedon-Fekjær og medarbeidere sett at LXR gjennom å regulere andre gener kan øke dannelsen, opptaket og aktiveringen av fettsyrer i morkakeceller. De identifiserte at et gen (acyl-CoA synthetase 3) som aktiverer fettsyrer, er direkte regulert av LXR. Dette genet ser ut til å være viktig for LXR–mediert aktivering av fettsyrer og transport av fettsyrer over morkaken. Videre ser de at både LXRalpha og LXRbeta er lavere uttrykt i morkaken hos gravide med svangerskapsforgiftning enn hos friske gravide. Dette antyder at uttrykket av LXR i morkaken kanskje kan være en faktor involvert i svangerskapsforgiftning. Resultatene av studien antyder at LXR kan ha en regulerende rolle i morkaken og øker vår forståelse for molekylære mekanismer involvert i regulering av fettsyremetabolisme og transport i morkaken via LXR.
The nuclear receptors liver X receptors (LXR� and �) are key regulators of lipid metabolism in many tissues, but the functional significance of the LXRs in placenta is largely unknown.
This thesis investigates the expression and regulatory roles of transcription factors LXR� and � in healthy and preeclamptic placentas as well as in placental trophoblast cells, in order to increase the knowledge of the molecular mechanisms involved in placental fatty acid uptake and metabolism. This knowledge could be important in order to better understand and possibly prevent adverse feto-placental growth and development.
This thesis showed that the expression of both LXR� and � in placental trophoblast cells was decreased in placental tissue from pregnancies complicated by preeclampsia. These results suggest a possible role for LXR� and � in the preeclamptic situation. The thesis further demonstrated that activation of LXR increases fatty acid biosynthesis, uptake and activation processes in placental trophoblast cells. The acyl-CoA synthetase ACSL3 was discovered as a new direct LXR target gene, and silencing of ACSL3 suggests that ACSL3 is important for the LXR-mediated increase in fatty acid activation and uptake in placental trophoblast cells. The results presented in this thesis suggest that LXR may have regulatory roles in placenta. Studies presented in this thesis have increased our understanding of the molecular mechanisms that may be involved in regulation of fatty acid metabolism and transport in placenta via LXR.
List of papers
Paper I: Weedon-Fekjaer MS, Duttaroy AK, Nebb HI. Liver X receptors mediate inhibition of hCG secretion in a human placental trophoblast cell line. Placenta. 2005 Nov; 26(10):721-8 The paper is not available in DUO. The published version is available at: https://doi.org/10.1016/j.placenta.2004.10.005 |
Paper II: Weedon-Fekjaer MS, Dalen KT, Solaas K, Staff AC, Duttaroy AK, Nebb HI. Activation of LXR increases fatty acid uptake through direct regulation of ACSL3 in placental trophoblast cells. Submitted. The paper is not available in DUO. |
Paper III: Weedon-Fekjaer MS, Johnsen GM, Sugulle M, Nebb HI, Duttaroy AK, Staff AC. Expression of liver X receptors in pregnancies complicated by preeclampsia. Under revision for resubmission to Placenta. The paper is not available in DUO. |