3,5,3′-Triiodo-L-Thyronine- and 3,5-Diiodo-L-Thyronine- Affected Metabolic Pathways in Liver of LDL Receptor Deficient Mice

Abstract

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.

3,5-Diiodo-L-Thyronine Exerts Metabolically Favorable Effects on Visceral Adipose Tissue of Rats Receiving a High-Fat Diet

“…On the other hand, annexins are calcium-dependent phospholipid binding proteins that may regulate various signaling pathways [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. The repressing impact of 3,5-T2 treatment on such a protein seems coherent with the previously reported effect of the iodothyronine on cellular calcium homeostasis [ 73 , 74 ].…”

Both 3,5-Diiodo-L-Thyronine and 3,5,3′-Triiodo-L-Thyronine Prevent Short-term Hepatic Lipid Accumulation via Distinct Mechanisms in Rats Being Fed a High-Fat Diet

“…In the same animal model used here, an increase in heart rate was observed starting from a dose of 75 μg/100 g BW during a 3-month treatment period (Padron et al, 2014 ). In studies on mice higher doses were used ranging from 250 μg/100 g BW (Jonas et al, 2015 ) to 1,250 μg/100 gBW (Moreno et al, 2016 ; da Silva Teixeira et al, 2017 ). Because the affinity of T2 for TRs is very low but cannot be completely ruled out (Ball et al, 1997 ; Mendoza et al, 2013 ), using high doses and long treatment periods, T3-like TR/TRE-mediated transcriptional effects may come into play, including downregulation of “slow” myosin heavy chain gene transcription in muscle (de Lange et al, 2008 ) and in heart (Edwards et al, 1994 ).…”

“…We have chosen to study the anti-lipidemic effects of T2 and T3 using a 1-week period of HFD feeding, leading to lipid accumulation but not to a possible irreversible hepatosteatosis. We chose the dose of T2 [25 μg/100 g body weight (BW)] because in our previous studies, this dose effectively prevented hepatic lipid accumulation without undesirable side effects, and is typically 10-fold lower than the doses used in other studies where cardiac side effects were observed (Padron et al, 2014 ; Jonas et al, 2015 ; Moreno et al, 2016 ). We chose a 10-fold lower dose of T3 (2.5 μg/100 g BW) because it is known that at this dose, T3 activates transcription through TRs/TREs without thyrotoxic effects (Senese et al, 2014 ).…”

Bioenergetic Aspects of Mitochondrial Actions of Thyroid Hormones

“…In rat skeletal muscle, T2 has resulted to stimulate mitochondrial uncoupling [126,130]. Interestingly, metabolic and lipid-lowering effects of T2 have also been shown in mice [131][132][133].…”