3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice
3,5,3’-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2), when administered to a model of familial hypercholesterolemia, i.e. low density lipoprotein receptor (LDLr)-knockout (Ldlr-/-) mice fed with a Western type diet (WTD), dramatically reduce circulating total and very low-density lipoprot...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-11-01
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| Series: | Frontiers in Physiology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphys.2016.00545/full |
| _version_ | 1819020253240229888 |
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| author | Maria Moreno Elena Silvestri Maria Coppola Ira J. Goldberg Li-Shin Huang Anna Maria Salzano Fulvio D’Angelo Joel R. Ehrenkranz Fernando Goglia |
| author_facet | Maria Moreno Elena Silvestri Maria Coppola Ira J. Goldberg Li-Shin Huang Anna Maria Salzano Fulvio D’Angelo Joel R. Ehrenkranz Fernando Goglia |
| author_sort | Maria Moreno |
| collection | DOAJ |
| description | 3,5,3’-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2), when administered to a model of familial hypercholesterolemia, i.e. low density lipoprotein receptor (LDLr)-knockout (Ldlr-/-) mice fed with a Western type diet (WTD), dramatically reduce circulating total and very low-density lipoprotein/LDL cholesterol with decreased liver apolipoprotein B (ApoB) production. The aim of the study was to highlight putative molecular mechanisms to manage cholesterol levels in the absence of LDLr. A comprehensive comparative profiling of changes in expression of soluble proteins in livers from Ldlr-/- mice treated with either T3 or T2 was performed. From a total proteome of 450 liver proteins, 25 identified proteins were affected by both T2 and T3, 18 only by T3 and 9 only by T2. Using in silico analyses, an overlap was observed with 11/14 pathways common to both iodothyronines, with T2 and T3 preferentially altering sub-networks centered around hepatocyte nuclear factor 4 α (HNF4α) and peroxisome proliferator-activated receptor α (PPARα), respectively. Both T2 and T3 administration significantly reduced nuclear HNF4α protein content, while T2, but not T3, decreased the expression levels of the HNFα transcriptional coactivator PGC-1α. Lower PPARα levels were found only following T3 treatment while both T3 and T2 lowered liver X receptor α (LXRα) nuclear content. Overall, this study, although it was not meant to investigate the use of T2 and T3 as a therapeutic agent, provides novel insights into the regulation of hepatic metabolic pathways involved in T3- and T2-driven cholesterol reduction in Ldlr-/- mice. |
| first_indexed | 2024-12-21T03:48:16Z |
| format | Article |
| id | doaj.art-6e18555c9a5341b89f4c12b64de0b246 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-21T03:48:16Z |
| publishDate | 2016-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-6e18555c9a5341b89f4c12b64de0b2462022-12-21T19:17:01ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2016-11-01710.3389/fphys.2016.005452298203,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient miceMaria Moreno0Elena Silvestri1Maria Coppola2Ira J. Goldberg3Li-Shin Huang4Anna Maria Salzano5Fulvio D’Angelo6Joel R. Ehrenkranz7Fernando Goglia8University of SannioUniversity of SannioUniversity of SannioColumbia UniversityColumbia UniversityNational Research CouncilBiogemIntermountain HealthcareUniversity of Sannio3,5,3’-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2), when administered to a model of familial hypercholesterolemia, i.e. low density lipoprotein receptor (LDLr)-knockout (Ldlr-/-) mice fed with a Western type diet (WTD), dramatically reduce circulating total and very low-density lipoprotein/LDL cholesterol with decreased liver apolipoprotein B (ApoB) production. The aim of the study was to highlight putative molecular mechanisms to manage cholesterol levels in the absence of LDLr. A comprehensive comparative profiling of changes in expression of soluble proteins in livers from Ldlr-/- mice treated with either T3 or T2 was performed. From a total proteome of 450 liver proteins, 25 identified proteins were affected by both T2 and T3, 18 only by T3 and 9 only by T2. Using in silico analyses, an overlap was observed with 11/14 pathways common to both iodothyronines, with T2 and T3 preferentially altering sub-networks centered around hepatocyte nuclear factor 4 α (HNF4α) and peroxisome proliferator-activated receptor α (PPARα), respectively. Both T2 and T3 administration significantly reduced nuclear HNF4α protein content, while T2, but not T3, decreased the expression levels of the HNFα transcriptional coactivator PGC-1α. Lower PPARα levels were found only following T3 treatment while both T3 and T2 lowered liver X receptor α (LXRα) nuclear content. Overall, this study, although it was not meant to investigate the use of T2 and T3 as a therapeutic agent, provides novel insights into the regulation of hepatic metabolic pathways involved in T3- and T2-driven cholesterol reduction in Ldlr-/- mice.http://journal.frontiersin.org/Journal/10.3389/fphys.2016.00545/full•Iodothyronines•liver•cholesterol•LDL receptor•proteomics. |
| spellingShingle | Maria Moreno Elena Silvestri Maria Coppola Ira J. Goldberg Li-Shin Huang Anna Maria Salzano Fulvio D’Angelo Joel R. Ehrenkranz Fernando Goglia 3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice Frontiers in Physiology •Iodothyronines •liver •cholesterol •LDL receptor •proteomics. |
| title | 3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice |
| title_full | 3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice |
| title_fullStr | 3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice |
| title_full_unstemmed | 3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice |
| title_short | 3,5,3’-triiodo-L-thyronine- and 3,5-diiodo-L-thyronine- affected metabolic pathways in liver of LDL receptor deficient mice |
| title_sort | 3 5 3 triiodo l thyronine and 3 5 diiodo l thyronine affected metabolic pathways in liver of ldl receptor deficient mice |
| topic | •Iodothyronines •liver •cholesterol •LDL receptor •proteomics. |
| url | http://journal.frontiersin.org/Journal/10.3389/fphys.2016.00545/full |
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