Cellular Aspects of Intestinal Lipoprotein Assembly in Psammomys Obesus

Abstract

Although postprandial hypertriglyceridemia is a major contributing factor in the development of atherosclerosis, little information is available on the effect of insulin resistance and diabetes on intestinal fat transport. The aim of the present study was to examine intracellular events that govern lipid transport and apolipoprotein (apo) B-48 -containing lipoprotein assembly in the small intestine of Psammomys obesus, a model of nutritionally induced insulin resistance and type 2 diabetes. Animals with normoglycemia/hyperinsulinemia and hyperglycemia/hyperinsulinemia exhibited high levels of triglycerides (TGs) in the plasma and intestine and postprandial plasma chylomicrons and apo B-48 compared with normoglycemic/normoinsulinemic animals. In vitro studies, using cultured jejunal explants incubated with either [ 14 C]oleic acid or [ 35 S]methionine, revealed their higher efficiency in de novo TG synthesis, apo B-48 biogenesis, and TG-rich lipoprotein assembly. Accordingly, enhanced monoacylglycerol and diacylglycerol acyltransferase activity was also discernible and concomitant with an increased content of L-fatty acid binding protein and in vivo chylomicron production rates. However, both the I-fatty acid binding protein amount and the apo B-48 proteasomal degradative pathway were decreased. Overall, our findings show that the development of an insulin-resistant/diabetic state in Psammomys obesus triggers the whole intra-enterocyte machinery, leading to lipoprotein assembly and favoring the intestinal oversecretion of apo B-48-lipoproteins, which may contribute to characteristic hypertriglyceridemia.

Overproduction of intestinal lipoprotein containing apolipoprotein B-48 in Psammomys obesus: impact of dietary n-3 fatty acids

“…In Group C, glycaemia can no longer be compensated for, in spite of the extraordinary elevation in plasma insulin. Recently, we demonstrated that the development of insulin-resistant and type 2 diabetic states led to intestinal oversecretion of apo B-48 lipoproteins in Psammomys obesus gerbils [18]. The results of the present investigation indicate the beneficial effects of diets enriched with n-3 FA on body weight, hyperglycaemia, hyperinsulinaemia and hyperlipidaemia.…”

“…Since proteasomal degradation of apo B plays a regulatory role in the early stages of apo B biosynthesis, we wondered whether this pathway is triggered by n-3 FA. The addition of N-acetyl-leucylnorleucinat and lactacystin as proteasomal inhibitors [18] suppressed the differences observed among groups, regardless of dietary regimen (Fig. 7b).…”

“…Although the physiological basis of metabolic dyslipidaemia appears to be hepatic overproduction of apo-B-containing VLDL particles [46,47], emerging evidence suggests that intestinal overproduction of apo-B-48-containing lipoproteins in insulin-resistant states may be an important contributor to the elevation of circulating triglyceride-rich lipoproteins [17,18,48]. The present study demonstrated that intestinal cells, like hepatocytes [49,50], responded to n-3 FA and decreased the output of triglyceride-rich lipoproteins by lowering the synthesis of apo B-48 and by inhibiting the new formation of lipids.…”

“…Relatively little attention has been given to the mechanisms behind postprandial triglycerides. However, the raised fasting triglyceride-rich lipoproteins often found in diabetes and associated with apo B-48 may be derived from increased intestinal chylomicron production [17,18]. According to these recent studies, synthesis rather than clearance may be the major cause of the increase in atherogenic postprandial particles in people with insulin resistance and type 2 diabetes.…”

Avancées dans la dissection fonctionnelle du transport intestinal des lipides

“…La voie protéolytique du protéasome représente la stratégie de vigilance majeure empruntée par la cellule pour limiter la production de l'apo B. Nos recherches nous ont amenés à constater que l'intestin peut contribuer à augmenter simultanément la synthèse de l'apo B-48 et les lipoprotéines riches en TG lors de la résistance à l'insuline et du diabète de type 2. Ce phénomène, contribuant à la dyslipidémie diabétique, peut être expliqué par une diminution de la dégradation de l'apoB, assurée par le dysfonctionnement du système ubiquitine-protéasome [38].…”