Dataset Information

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

SUBMITTER: Moreno M

PROVIDER: S-EPMC5112267 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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

Moreno Maria M Silvestri Elena E Coppola Maria M Goldberg Ira J IJ Huang Li-Shin LS Salzano Anna M AM D'Angelo Fulvio F Ehrenkranz Joel R JR Goglia Fernando F

Frontiers in physiology 20161117

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 ...[more]

PMID: 27909409

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Project description:Thyroid hormone mimetics are alluring potential therapies for diseases like dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. Though diiodothyronines are thought inactive, pharmacologic treatment with 3,5- Diiodo-L-Thyronine (T2) reportedly reduces hepatic lipid content and improves glucose tolerance in fat-fed male rats. To test this, male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 (0.25 mg/kg-d) or vehicle. Neither 10 nor 30 days of T2 treatment had an effect on weight, adiposity, plasma fatty acids, or hepatic steatosis. Insulin action was quantified in vivo by a hyperinsulinemic-euglycemic clamp. T2 did not alter fasting plasma glucose or insulin concentration. Basal endogenous glucose production (EGP) rate was unchanged. During the clamp, there was no difference in insulin stimulated whole body glucose disposal. Insulin suppressed EGP by 60% ± 10 in T2-treated rats as compared with 47% ± 4 suppression in the vehicle group (p = 0.32). This was associated with an improvement in hepatic insulin signaling; insulin stimulated Akt phosphorylation was ~2.5 fold greater in the T2-treated group as compared with the vehicle-treated group (p = 0.003). There was no change in expression of genes thought to mediate the effect of T2 on hepatic metabolism, including genes that regulate hepatic lipid oxidation (ppara, carnitine palmitoyltransferase 1a), genes that regulate hepatic fatty acid synthesis (srebp1c, acetyl coa carboxylase, fatty acid synthase), and genes involved in glycolysis and gluconeogenesis (L-pyruvate kinase, glucose 6 phosphatase). Therefore, in contrast with previous reports, in Sprague Dawley rats fed an unsaturated fat diet, T2 administration failed to improve NAFLD or whole body insulin sensitivity. Though there was a modest improvement in hepatic insulin signaling, this was not associated with significant differences in hepatic insulin action. Further study will be necessary before diiodothyronines can be considered an effective treatment for NAFLD and dyslipidemia.

Project description:Growing evidence shows that, among triiodothyronine derivatives, 3,5 diiodo-L-thyronine (T(2)) plays an important role in energy metabolism and fat storage. In the present study, short-term effects of T(2) administration to hypothyroid rats on fatty acid oxidation rate and bioenergetic parameters were investigated. Within 1 h following T(2) injection, state 3 and state 4 respiration rates, which were reduced in hypothyroid mitochondria, were noticeably increased particularly in succinate- with respect to glutamate/malate-energized mitochondria. Maximal respiratory activity, observed when glutamate/malate/succinate were simultaneously present in the respiratory medium, was significantly stimulated by T(2) treatment. A T(2)-induced increase in respiratory rates was also observed when palmitoyl-CoA or L-palmitoylcarnitine were used as substrates. No significant change in respiratory control index and ADP/O ratio was observed. The activities of the mitochondrial respiratory chain complexes, especially Complex II, were increased in T(2)-treated rats. In the latter, Complex V activities, assayed in both ATP synthesis and hydrolysis direction, were enhanced. The rate of fatty acid oxidation, followed by conversion of [(14)C]palmitate to CO(2) and ketone bodies, was higher in hepatocytes isolated from T(2)-treated rats. This increase occurs in parallel with the raise in the activity of carnitine palmitoyltransferase-I, the rate limiting enzyme of fatty acid β-oxidation, assayed in situ in digitonin-permeabilized hepatocytes. Overall, these results indicate that T(2) rapidly increases the ability of mitochondria to import and oxidize fatty acids. An emerging idea in the literature is the ability of T(2) to reduce adiposity and dyslipidemia and to prevent the development in liver steatosis. The results of the present study, showing a rapid T(2)-induced increase in the ability of mitochondria to import and oxidize fatty acids, may contribute to understand the biochemical mechanisms of T(2)-metabolic effects.

Project description:Hyperlipidemic state-associated perturbations in the network of factors controlling mitochondrial functions, i. e., morphogenesis machinery and metabolic sensor proteins, produce metabolic inflexibility, insulin resistance and reduced oxidative capacity in skeletal muscle. Moreover, intramyocellular lipid (IMCL) accumulation leads to tissue damage and inflammation. The administration of the naturally occurring metabolite 3,5-diiodo-L-thyronine (T2) with thyromimetic actions to high fat diet (HFD)-fed rats exerts a systemic hypolipidemic effect, which produces a lack of IMCL accumulation, a shift toward glycolytic fibers and amelioration of insulin sensitivity in gastrocnemius muscle. In this study, an integrated approach combining large-scale expression profile and functional analyses was used to characterize the response of skeletal muscle mitochondria to T2 during a HFD regimen. Long-term T2 administration to HDF rats induced a glycolytic phenotype of gastrocnemius muscle as well as an adaptation of mitochondria to the fiber type, with a decreased representation of enzymes involved in mitochondrial oxidative metabolism. At the same time, T2 stimulated the activity of individual respiratory complex I, IV, and V. Moreover, T2 prevented the HFD-associated increase in the expression of peroxisome proliferative activated receptor γ coactivator-1α and dynamin-1-like protein as well as mitochondrial morphological aberrations, favoring the appearance of tubular and tethered organelles in the intermyofibrillar regions. Remarkably, T2 reverted the HDF-associated expression pattern of proinflammatory factors, such as p65 subunit of NF-kB, and increased the fiber-specific immunoreactivity of adipose differentiation-related protein in lipid droplets. All together, these results further support a role of T2 in counteracting in vivo some of the HFD-induced impairment in structural/metabolic features of skeletal muscle by impacting the mitochondrial phenotype.

Dataset Information

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

Publications

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

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