RESUMO
Liver fibrosis is the common outcome of many chronic liver diseases, resulting from altered cell-cell and cell-matrix interactions that promote hepatic stellate cell (HSC) activation and excessive matrix production. This study aimed to investigate functions of cellular communication network factor 2 (CCN2)/Connective tissue growth factor (CTGF), an extracellular signaling modulator of the CYR61/CTGF/Nov (CCN) family, in liver fibrosis. Tamoxifen-inducible conditional knockouts in mice and hepatocyte-specific deletion of this gene in rats were generated using the Cre-lox system. These animals were subjected to peri-central hepatocyte damage caused by carbon tetrachloride. Potential crosstalk of this molecule with a new profibrotic pathway mediated by the Slit2 ligand and Roundabout (Robo) receptors was also examined. We found that Ccn2/Ctgf was highly upregulated in periportal hepatocytes during carbon tetrachloride-induced hepatocyte damage, liver fibrosis and cirrhosis in mice and rats. Overexpression of this molecule was observed in human hepatocellular carcinoma (HCC) that were surrounded with fibrotic cords. Deletion of the Ccn2/Ctgf gene significantly reduced expression of fibrosis-related genes including Slit2, a smooth muscle actin (SMA) and Collagen type I during carbon tetrachloride-induced liver fibrosis in mice and rats. In addition, Ccn2/Ctgf and its truncated mutant carrying the first three domains were able to interact with the 7th -9th epidermal growth factor (EGF) repeats and the C-terminal cysteine knot (CT) motif of Slit2 protein in cultured HSC and fibrotic murine livers. Ectopic expression of Ccn2/Ctgf protein upregulated Slit2, promoted HSC activation, and potentiated fibrotic responses following chronic intoxication by carbon tetrachloride. Moreover, Ccn2/Ctgf and Slit2 synergistically enhanced activation of phosphatidylinositol 3-kinase (PI3K) and AKT in primary HSC, whereas soluble Robo1-Fc chimera protein could inhibit these activities. These observations demonstrate conserved cross-species functions of Ccn2/Ctgf protein in rodent livers. This protein can be induced in hepatocytes and contribute to liver fibrosis. Its novel connection with the Slit2/Robo signaling may have therapeutic implications against fibrosis in chronic liver disease.
RESUMO
Actualmente los fitoesteroles son adicionados a los alimentos industrializados, lo que aumenta su costo y por lo tanto limita su consumo. Este manuscrito tiene como objetivo identificar alimentos que son una fuente natural de fitoesteroles, así como también analizar cómo el ambiente y el manejo productivo modifican su contenido, relacionando estos aspectos con la salud. Los fitoesteroles son compuestos presentes en las plantas con propiedades hipocolesterolémicas, que pueden contribuir a prevenir las enfermedades cardiovasculares. La ingesta diaria estimada de fitoesteroles varía entre 160 y 500 mg/día, sin embargo su acción beneficiosa se logra con consumos de 1500 mg a 2400 mg diarios. Las semillas de oleaginosas y de cereales son las mayores fuentes naturales de fitoesteroles. El amaranto es considerado un pseudocereal y entre los cereales tiene la mayor concentración de fitoesteroles con 178 mg/100 g, valor 5 veces superior al de la harina de trigo. El ambiente modifica el contenido de fitoesteroles de los alimentos, la sequía y temperaturas altas duplican su contenido en las semillas; la fertilización nitrogenada y la fecha de siembra pueden provocar cambios, pero se requieren más estudios al respecto. La selección de genotipos con mayor contenido de fitoesteroles y el estudio de la interacción genotipo ambiente, permitirá la identificación de aquellos genotipos con adaptación local para este carácter. El manejo productivo podrá aumentar la oferta de alimentos naturales ricos en fitoesteroles, contribuyendo a una mayor oferta de alimentos protectores de la salud(AU)
Currently phytosterols are added to processed foods, which increase their cost and therefore limits its use. This manuscript aims to identify foods that are a natural source of phytosterols, as well as analyze how the environment and production management modify its content, linking these aspects with health. Phytosterols are compounds found in plants with hypocholesterolemic properties, which may help prevent cardiovascular diseases. The estimated daily intake of phytosterols varies between 160 and 500 mg/day, but its beneficial effect is achieved with 1,500 to 2,400 mg daily consumption. Oil and cereal seeds are the largest natural sources of phytosterols. Amaranth is considered a pseudocereal and among the cereals has the highest concentration of phytosterols with 178 mg/100 g, value 5 times higher than wheat flour. Environment modifies phytosterol content in food, drought and high temperatures can double their content in seeds; nitrogen fertilization and planting date can cause changes, but more studies are needed. The selection of genotypes with higher phytosterol content and studying the genotype x environment interaction, allow the identification of those genotypes with local adaptation for this character. The production management will increase the supply of natural foods rich in phytosterols, contributing to a greater supply of health protective foods(AU)
