Rol del enterocito en la dislipidemia de la diabetes mellitus tipo 2 / Role of the enterocyte in type 2 diabetes mellitus associated dyslipidemia

En la diabetes mellitus tipo 2 el aumento en la producción de quilomicrón en el estado post-prandial se asocia a mayor riesgo cardiovascular. La evidencia actual posiciona al enterocito como actor principal en la dislipemia de la diabetes mellitus tipo 2 debido a que aumenta la producción de apolipoproteína B-48 en respuesta a una elevación de ácidos grasos libres y glucosa. El metabolismo del quilomicrón se encuentra regulado por múltiples factores independientes además de la ingesta de grasa alimentaria. Entre estos factores se destacan las hormonas intestinales, como el péptido similar al glucagón tipo 1 que disminuye la producción de apolipoproteína B-48 y el péptido similar al glucagón tipo 2 que la aumenta. Por otro lado, la insulina inhibe de forma aguda la producción de quilomicrón en el sujeto sano mientras que en la diabetes mellitus tipo 2, este efecto está ausente. La comprensión de los factores reguladores emergentes de la secreción de quilomicrón permite vislumbrar nuevos mecanismos de control en su metabolismo y aportar estrategias terapéuticas focalizadas en la hiperlipidemia posprandial en la diabetes mellitus tipo 2 con la reducción del riesgo cardiovascular.

In type 2 diabetes mellitus there is an overproduction of chylomicron in the postprandial state that is associated with increased cardiovascular risk. Current evidence points out a leading role of enterocyte in dyslipidemia of type 2 diabetes mellitus, since it increases the production of apolipoprotein B-48 in response to a raise in plasma free fatty acids and glucose. The chylomicron metabolism is regulated by many factors apart from ingested fat, including hormonal and metabolic elements. More recently, studies about the role of gut hormones, have demonstrated that glucagon-like peptide-1 decreases the production of apolipoprotein B-48 and glucagon-like peptide-2 enhances it. Insulin acutely inhibits intestinal chylomicron production in healthy humans, whereas this acute inhibitory effect on apolipoprotein B-48 production is blunted in type 2 diabetes mellitus. Understanding these emerging regulators of intestinal chylomicron secretion may offer new mechanisms of control for its metabolism and provide novel therapeutic strategies focalized in type 2 diabetes mellitus postprandial hyperlipidemia with the reduction of cardiovascular disease risk.

Iron-zinc interaction during uptake in human intestinal Caco-2 cell line: Kinetic analyses and possible mechanism.

Iron and zinc interact at the enterocyte during absorption, but the mechanism(s) remain elusive. The aim was, therefore, to understand the mechanism of interaction using kinetic analyses of iron and zinc uptake, individually and in combination under normal and altered cellular mineral concentrations in human intestinal Caco-2 cell line. Striking differences in kinetic parameters were observed between iron and zinc uptake. Iron uptake followed a two-component model, while zinc uptake followed a three-component model. Iron uptake had a Km of 3.6 µM and Vmax of 452 pmol/mg protein/min, while zinc uptake had a Km of 42 µM and Vmax of 3.09 pmol/mg protein/min. Zinc dose-dependently inhibited iron uptake through mixed-inhibition but iron marginally increased zinc uptake. Cellular zinc repletion doubled iron uptake and eliminated inhibition, but zinc depletion decreased iron uptake. Iron pre-treatment had no effect on zinc uptake. Based on these results, a two-transporter model of iron uptake, comprising the apical iron uptake transporter divalent metal ion transporter-1 (DMT-1) and an unknown putative transporter was derived. This model for DMT-1 was verified by immunoblotting. These results implied that cellular zinc status profoundly influenced iron uptake and its interactions with zinc during uptake. DMT-1 might not simultaneously transport iron and zinc, providing a mechanistic basis for observed interactions.

Possible roles of the hereditary hemochromatosis protein, HFE, in regulating cellular iron homeostasis

Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European descent. Over 83 percent of the cases of HH result from a single mutation of a Cys to Tyr in the HH protein, HFE. This mutation causes a recessive disease resulting in an accumulation of iron in selected tissues. Iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. The mechanism by which HFE influences iron homeostasis in cells and in the body remains elusive. Lack of functional HFE in humans produces the opposite effects in different cell types in the body. In the early stages of the disease, Kupffer cells in the liver and enterocytes in the intestine cells are iron depleted and have low intracellular ferritin levels, whereas hepatocytes in the liver are iron overloaded and have high intracellular iron levels. This review gives the background and a model as to possible mechanisms of how HFE could exert different effects on iron homeostasis in different cell types.

Regulation of transepithelial transport of iron by hepcidin

Hepcidin (Hepc) is a 25 amino acid cationic peptide with broad antibacterial and antifungal actions. A likely role for Hepc in iron metabolism was suggested by the observation that mice having disruption of the gene encoding the transcription factor USF2 failed to produce Hepc mRNA and developed spontaneous visceral iron overload. Lately, Hepc has been considered the stores regulator, a putative factor that signals the iron content of the body to intestinal cells. In this work, we characterized the effect of Hepc produced by hepatoma cells on iron absorption by intestinal cells. To that end, human Hepc cDNA was cloned and overexpressed in HepG2 cells and conditioned media from Hepc-overexpressing cells was used to study the effects of Hepc on intestinal Caco-2 cells grown in bicameral inserts. The results indicate that Hepc released by HepG2 inhibited apical iron uptake by Caco-2 cells, probably by inhibiting the expression of the apical transporter DMT1. These results support a model in which Hepc released by the liver negatively regulates the expression of transporter DMT1 in the enterocyte.