MECANISMOS MOLECULARES ENVOLVIDOS NA REVERSÃO DA HIPERTRIGLICERIDEMIA E ESTEATOSE HEPÁTICA DE ANIMAIS OBESOS TRATADOS COM O EXTRATO HIDROALCOÓLICO DAS FOLHAS DE SYZYGIUM CUMINI.

Abstract

Obesity is considered the epidemic of the 21 st century, and its hepatic manifestation, nonalcoholic fatty live disease (NAFLD), is present in more than 80 % of obese people. Therefore, NAFLD is a public health problem, since that is direct risk factor for cardiovascular diseases, mainly because of its close relationship with dyslipidemias. The plant species Syzygium cumini, whose popular name is jambolan, is widely used in traditional medicine for disorders associated with obesity such as diabetes mellitus and dyslipidemias. In previous paper from our group, the polyphenol-rich hydroethanolic extract of S. cumini (HESc) leaves reduced NAFLD and hypertriglyceridemia of monosodium L-glutamate (MSG)-induced obesity rats. Thus, the aim of this work was to investigate possible mechanisms of action of the HESc on the hepatic lipid metabolism of MSG-obese rats. In the first study of this doctoral dissertation, when male MSGobese Wistar rats were orally treated with HESc (0.5 or 1.0 g/kg/day) or vehicle (0.1 ml/100 g/day) for 8 weeks there was decreasing white adipose tissue (WAT) accumulation without altering food intake. The treatment also reduced blood levels of fasting glucose, total cholesterol, triacylglycerols (TAG) and free fatty acids, as well as the TyG index. The HESc restored the hepatic steatosis of obese rats and halved the TAG content of very low-density lipoproteins (VLDL). In liver was seen protein expression reduction of splicing of X-box binding protein 1 (XBP-1s), protein disulfide isomerase (PDI) and microsomal triglyceridetransfer protein (MTP), which are part of the TAG secretion pathway. This effect was corroborated by the acute inhibition of serum TAG accumulation promoted by HESc after injection (0.3 g/kg, i.p.) of Triton WR1339 in other male Wistar rats. In another study, treatment for 4 weeks with the lowest dose (0.5 g/kg/day) in MSG-obese Swiss mice did not alter the dietary pattern and reduced BAT, in addition to improving the lipolytic activity of this tissue. Similarly in rats, HESc improved glycemia, serum lipid profile, and NAFLD. Moreover, treatment improved insulin sensitivity by decreases of HOMA1-IR and TyG indices, and serum insulin, and increases kITT. In the molecular analysis of the liver, HESc declined the gene expression of lipogenic transcription factors (sterol response element-binding protein 1c and peroxisome proliferator-activated receptor γ), and enzymes (fatty acid synthase and diacylglycerol acyltransferase 2), as well as markers for TAG exportation (apolipoprotein B and MTP). In addition, there was gene downregulation of an endoplasmic reticulum (ER) stress arm in treated animals, with reductions of PKR-like endoplasmic reticulum kinase (PERK) and nuclear factor erythroid 2-related factor. First of all, these data confirm the efficacy of HESc in the reversion of NAFLD and hypertriglyceridemia from MSG-obese rodents. And as a novelty in literature, this work suggest that theses effects should be partly due to improved insulin sensitivity in these animals, but also by the downregulation of ER stress pathways, such as XBP-1s and PERK, which are important inducers of secretion and synthesis of TAG in the liver, respectively. Therefore, this dissertation highlights the importance of ER stress as a therapeutic target for changes in hepatic lipid metabolism, in addition to contributing to the validation of the efficacy of S. cumini on these obesity-associated disorders.