PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

Functional Interaction of Spexin and Adiponectin Forming a Local Feedbackin Goldfish Hepatocytes for Feeding Regulation

Spexin (SPX), a neuropeptide with pleiotropic functions, has been confirmed to be a novel satiety factor in fish models. Adiponectin (AdipoQ), the most abundant adipokine in circulation, is involved in lipid and glucose metabolism and its insulin-sensitizing, cardioprotective, and anti-inflammatory actions are also well-documented. However, the interaction between SPX and AdipoQ has not be reported and very little is known regarding the functions of AdipoQ in non-mammalian species. In this study, AdipoQ was cloned in goldfish and found to be widely expressed at tissue level including the liver. Sequence alignment and in silico protein modelling revealed that its a.a. sequence and 3D protein structure were highly comparable to the mammalian counterparts. Recombinant protein of goldfish AdipoQ was expressed in E. coli and IP injection of the protein purified could suppress foraging activity and food intake in goldfish. Food intake in goldfish, interestingly, could elevate plasma levels of SPX and AdipoQ with parallel rises of their transcript expression in the liver. In primary culture of goldfish hepatocytes, SPX treatment was shown to induce protein phosphorylation of MEK1/2 and ERK1/2 with a parallel rise in AdipoQ mRNA level. SPX-induced AdipoQ mRNA expression, however, was sensitive to the blockade of PLC/PKC, Ca2+/CaMK-II and MEK1/2/ERK1/2 but not cAMP/PKA cascades. In reciprocal experiments, AdipoQ treatment could induce protein phosphorylation of AMPK, Akt and P38 MAPK in goldfish hepatocytes. Meanwhile, AdipoQ was also effective in reducing SPX mRNA level and this inhibitory effect was negated by blocking the AMPK/PPAR, PI3K/Akt and P38 MAPK but not the MEK1/2/ERK1/2 or PLC/PKC pathways. Apparently, the PI3K/Akt and P38 MAPK cascades were functionally coupled with AMPK activation. These results imply that (i) AdipoQ, similar to SPX, can be induced by food intake and serve as a satiety signal in goldfish, (ii) AdipoQ expression in goldfish liver can be up-regulated by SPX via the PLC/PKC, Ca2+/CaMK-II and MEK1/2/ERK1/2 pathways, which may enhance the satiation response caused by SPX after food intake, and (iii) AdipoQ can inhibit SPX expression at hepatic level via the AMPK/PPAR, PI3K/Akt and P38 MAPK cascades, which may lead to signal termination of SPX. These findings, as a whole, suggest that AdipoQ production in goldfish liver not only can form a signal amplification step for the satiation response of SPX but also constitute a local feedback to turn off SPX signal at the hepatic level.

Antioxidant Activity of Entrapped alfa-tocopherol and Lutein in PLGA Nanoparticles in Wistar Rats

The hypercaloric diet leads to obesity which is a risk factor for developing many systemic diseases such as diabetes, cardiovascular diseases and cancer. The purpose of our study was to observe the antioxidants effects of entrapped alfa-tocopherol (vitamin E) and lutein in Poly Lactic-CO-Glycolic acid (PLGA) in Wistar rats that received 3 weeks hypercaloric diet. Hepatic and splenic lysates have been used to detect changes in total antioxidant capacity (TAC) and advanced oxidative protein products (AOPP). The AOPP liver levels were statistically decreased in the case of rats groups that received a daily dose of PLGA-lutein or PLGA-vitamin E versus the control group. The AOPP level was decreased but statistically insignificant in Wistar rats spleen who received a daily dose of PLGA-lutein. At hepatic level, TAC was statistically increased in rats groups that received a daily dose of vitamin E or lutein. An increased statistical level of TAC was observed in the spleen cell lysing in Wistar rats who received the daily dose of PLGA-vitamin E. Entrapment of vitamin E and lutein in PLGA structure has diminished the effects of hypercaloric diet and can be considered a attractive and promising approach to enhance the bioavailability and activity of poorly water soluble compounds.

Effect of trans-chalcone on hepatic IL-8 through the regulation of miR-451 in male rats

Objective. Trans-chalcone is a chalcone with hepatoprotective and anti-inflammatory effects. However, the mechanism of these positive effects, especially on miR-451 as an inflammatory regulator, is poorly understood. In this regard, this microRNA (miRNA) acts by inhibition of hepatic interleukin-8 (IL-8) production in the liver which is one of the main proinflammatory cytokines. Th is study for the first time examined the effect of trans-chalcone on miR-451/IL-8 pathway. Methods. In present study, 21 male rats were randomly divided into 3 groups (n=7 per each group): control which received solvent (NS), groups 2 (N2T) and 3 (N6T), which received transchalcone for 2 and 6 weeks, respectively. Hepatic level of miR-451 was measured by qRT-PCR. Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as well as hepatic level of IL-8 protein were measured. Results. Trans-chalcone decreased hepatic level of IL-8 protein and serum level of ALT aft er 2 weeks of treatment without significant change in hepatic miR-451. Moreover, it increased hepatic level of miR-451 and reduced hepatic IL-8 as well as AST and ALT aft er 6 weeks. Conclusion. Based on the results of present study, miR-451/IL-8 pathway is a possible mechanism for hepatoprotective action of trans-chalcone in long-term.

Rapid Clot Formation and Abnormal Fibrin Structure in a Symptomatic Patient Taking Fenfluramine

A 35-year-old woman experienced symptomatic calf pain while taking a combination of fenflu ramine and phentermine. All symptoms resolved when the medications were stopped, but pain returned when fenfluramine was restarted. Laboratory evaluation revealed mild elevations of aspartate aminotransferase and lactate dehydrogenase and a remarkably shortened prothrombin time (6.3 seconds). Additional studies revealed that the clots were composed of very thin fibrin fibers. All laboratory abnormalities, including the abnormal fibrin structure, completely resolved when fenfluramin was stopped. Direct addition of fenfluramine or phen termine to normal plasma did not alter either coagulation kinetics or fibrin structure, supporting the concept that the induced changes may have originated at the hepatic level. Clots composed of thin fibers are much more resistant to fibrinolysis, and could potentially put such patients at risk for thrombotic complications. This is the first report of clotting abnormalities associated with fenfluramine use. Subsequent to its use in this patient, fenfluramine was removed from clinical use due to reports of acquired valvular heart disease.