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.
Highlights
Familial hypercholesterolemia (FH) is a common inherited disorder resulting from mutations in the low-density lipoprotein receptor (LDLr) gene leading to defects in LDL cholesterol (LDL-C) clearance
Through a 2D-E-based proteomic approach, the hepatic pathways and the molecular mediators involved in the T2and T3- induced reductions in circulating cholesterol levels in Ldlr−/− mice were investigated
Increased endogenous T3 does not account for the effects of T2. It has been hypothesized on the basis of in vitro studies that THs mediate lowering of LDL-C primarily by increased hepatic expression of low density lipoprotein receptor (LDLr) (Lopez et al, 2007) and that they up regulate scavenger scavenger receptor-B1 (SR-B1) in mice (Johansson et al, 2005), very recently, we (Goldberg et al, 2012) and others (Lin et al, 2012) reported that THs can reduce serum cholesterol via a LDLrindependent mechanism
Summary
Familial hypercholesterolemia (FH) is a common inherited disorder resulting from mutations in the low-density lipoprotein receptor (LDLr) gene leading to defects in LDL cholesterol (LDL-C) clearance. One possible approach to cholesterol reduction is via activation of hepatic thyroid receptors (TRs) Both 3,5,3′,5′-tetraiodo-L-thyronine (T4), and 3,5,3′-triiodoL-thyronine (T3) (THs) reduce circulating cholesterol in animals and humans (Klein and Danzi, 2008; Angelin and Rudling, 2010). Several thyromimetics (i.e., GC1 and KB2115) have been developed that selectively activate TRβ, the predominant TR isoform in the liver that is primarily responsible for the effects on cholesterol and lipoprotein metabolism exerted by T3 (Johansson et al, 2005; Erion et al, 2007; Tancevski et al, 2010; Pramfalk et al, 2011) These compounds retard atherosclerosis progression in animals and exert favorable lipid-modulating effects in humans, while lacking THs-related thyrotoxic side-effects (Bakker et al, 1998; Erion et al, 2007; Baxter and Webb, 2009; Pedrelli et al, 2010). Side effects may limit its clinical use since the cholesterol-reducing thyrometic eprotirome (Ladenson et al, 2010) was recently shown to elevate circulating liver enzymes (Sjouke et al, 2014), a sign of liver damage and, development of eprotirome was terminated after cartilage damage was observed in a toxicological study in dogs
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