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 (LdIr(-/-)) 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 LdIr(-/-) 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 alpha (HNF4 alpha) and peroxisome proliferator-activated receptor alpha (PPAR alpha), respectively. Both T2 and T3 administration significantly reduced nuclear HNF4 alpha protein content, while T2, but not T3, decreased the expression levels of the HNF alpha transcriptional coactivator PGC-1 alpha. Lower PPAR alpha levels were found only following T3 treatment while both T3 and T2 lowered liver X receptor alpha (LXR alpha) 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 LdIr(-/-) mice.