Impact of citrus flavanones on thyroid homeostasis and lipid status of old-aged rats

Citrusni flavanoni, naringenin (NAR) i hesperetin (HES), su polifenolne supstance koje zbog sterne sličnosti sa endogenim tiroksinom (T4) mogu da interferiraju sa aktivnošću tiroidne peroksidaze, ključnog enzima u biosintezi tiroidnih hormona. Sa starenjem se povećava osetljivost tiroidne osovine na efekte egzogenih supstanci i raste rizik od nastanka hroničnih bolesti usled opadanja detoksikacione sposobnosti i akumulacije lipida u jetri. Cilj ove doktorske disertacije bio je da se ispita uticaj NAR i HES na tiroidnu homeostazu i lipidni status 24 meseca starih mužjaka pacova Wistar soja. Supstance su aplikovane per os u dozi od 15 mg/kg t.m., tokom četiri nedelje. Rezultati ove disertacije su pokazali da NAR i HES uzrokuju strukturne i ultrastrukturne promene štitaste žlezde starih mužjaka pacova, povećavaju imunohistohemijsku ekspresiju tiroglobulina za koji je vezan T4 i vaskularnog endotelijalnog faktora rasta. Ekspresija trijodtironinom (T3) regulisanih gena u jetri je snižena nakon tretmana citrusnim flavanonima. U serumu, NAR je povisio koncentracije TSH i HDL, dok je koncentracija antioksidativnih enzima jetre snižena nakon oba tretmana. Uočava se desaturacija masnih kiselina u fosfolipidima membrane hepatocita, povećanje udela n-3, a sniženja zastupljenosti n-6 masnih kiselina nakon primene oba citrusna flavanona. Smanjuje se lipidna peroksidacija membrane hepatocita i poboljšava antioksidativna zaštita u jetri nakon NAR i HES tretmana. NAR je ispolji jači efekat, jer je uticao na aktivnost, gensku i proteinsku ekspresiju antioksidativnih enzima, i parametre redoks ravnoteže, dok je HES pojačao antioksidativnu zaštitu, ali u manjoj meri. Upotreba citrusnih flavanona uzrokuje neželjene efekte - subkličničku hipotireozu koju prate povišen nivo TSH i smanjena ekspresija T3 regulisanih gena u jetri. Međutim, sa stanovišta desaturacije membrane hepatocita i poboljšanja antioksidativne zaštite u jetri, upotreba NAR i HES se može smatrati korisnom, imajući u vidu uticaj ovih promena na produženje dužine životnog veka.Citrus flavanones, naringenin (NAR) and hesperetin (HES), are polyphenolic substances, structurally similar to endogenous thyroxine (T4), that can interfere with the activity of thyroid peroxidase, the key enzyme in thyroid hormone biosynthesis. With aging, thyroid axis sensitivity to the effects of exogenously applied substances increases and the risk of chronic diseases raises due to reduced detoxification ability and the accumulation of lipids in the liver. The aim of this doctoral dissertation was to examine the impact of NAR and HES on thyroid homeostasis and the lipid status of 24 monthsold Wistar male rats. The substances were administered per os at a dose of 15 mg/kg b.w., for four weeks. The results of this dissertation have shown that NAR and HES cause structural and ultrastructural changes in the thyroid gland of old male rats, increasing the immunohistochemical expression of T4 bounded to thyroglobulin as well as of vascular endothelial growth factor. Expression of triiodothyronine (T3) regulated genes in the liver were decreased after treatment with citrus flavanones. In the serum, the NAR increased concentrations of TSH and HDL, while the concentration of liver antioxidative enzymes was reduced after both treatments. The desaturation of fatty acids in the hepatocyte membrane phospholipids, the increase in the proportion of n-3, and the reduction in the presence of n-6 fatty acids after application of both citrus flavanones is observed. Lipid peroxidation of the hepatocyte membrane is reduced and the antioxidant protection is improved in the liver after NAR and HES treatments. The NAR has a stronger effect, as it has affected the activity, gene and protein expression of antioxidant enzymes, as well as the parameters of redox balance, while HES enhanced antioxidant protection, but to a less degree. The use of citrus flavanones causes unwanted effects - subclinical hypothyrosis followed by elevated TSH and reduced expression of T3 regulated genes in the liver. However, from the perspective of the hepatocyte membrane desaturation and the enhancement of antioxidant protection in the liver, the use of NAR and HES can be considered useful, given that the effects of these changes are associated with the extend life span