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

Abstract

Aims/hypothesis Emerging evidence underscores the important role of the small intestine in the pathogenesis of dyslipidaemia in insulin resistance and type 2 diabetes. We therefore tested the hypothesis that n-3 fatty acids improve the various events governing intra-enterocyte lipid transport in Psammomys obesus gerbils, a model of nutritionally induced metabolic syndrome. Materials and methods Experiments were carried out on Psammomys obesus gerbils that were assigned to an isocaloric control diet and a diet rich in fish oil for 6 weeks. Results Increased dietary intake of fish oil lowered body weight and improved hyperglycaemia and hyperinsulinaemia. It simultaneously decreased de novo intestinal lipogenesis and lipid esterification of the major lipid classes, e.g. triglycerides, phospholipids and cholesteryl esters, particularly in insulinresistant and diabetic animals. Accordingly, lessened activity of monoacylglycerol and diacylglycerol acyltransferase was recorded. As assessed in cultured jejunal explants incubated with either [ 14 C]-oleic acid or [ 35 S]-methionine, fish oil feeding resulted in diminished triglyceride-rich lipoprotein assembly and apolipoprotein (apo) B-48 biogenesis, respectively. The mechanisms did not involve apo B-48 transcription or alter the gene expression and activity of the critical microsomal triglyceride transfer protein. Rather, the suppressed production of apo B-48 by n-3 fatty acids was associated with intracellular proteasome-mediated posttranslational downregulation in insulin-resistant and diabetic animals. Conclusions/interpretation Our data highlight the beneficial impact of n-3 fatty acids on adverse effects of the metabolic syndrome and emphasise their influence on intestinal lipid transport, an effect which may limit postprandial lipaemia and the risk of atherosclerosis.

Key intestinal genes involved in lipoprotein metabolism are downregulated in dyslipidemic men with insulin resistance

“…Recent fi ndings from animal models of IR are consistent with data from humans that have revealed the overproduction of intestinal apoB-48-containing lipoproteins ( 10,11 ). Studies have also consistently supported the concept that inducing IR in various animal models is associated with signifi cant upregulation of the expression of key intestinal genes involved in lipid and lipoprotein metabolism ( 12,13 ).…”

Increased hepatic lipogenesis in insulin resistance and Type 2 diabetes is associated with AMPK signalling pathway up-regulation in Psammomys obesus

“…Furthermore, our observations pointed to an undoubtedly important role of the liver in the pathogenesis of metabolic disorders in the progression of nutritionally induced 'diabesity' in P. obesus since the development of these conditions triggered the whole intra-hepatocyte machinery, leading to lipoprotein assembly and favouring the oversecretion of apolipoprotein B-100-lipoproteins [23]. Beneficial effects of diets enriched with n-3 FA were noted on body weight, hyperglycaemia, hyperinsulinaemia and hyperlipidaemia, as well as on intestinal lipogenesis, lipid esterification and de novo apo B-48 synthesis [24,25]. Favourable n-3 FAs clearly impact on the overproduction of intestinal TAG (triacylglycerol)-rich lipoproteins.…”

Disturbed Chylomicron Metabolism in Type 2 Diabetes - A Preventable Cause of Atherosclerosis?

“…There was a negative correlation between both ABCG5 and G8 and chylomicron cholesterol [83]. In the Psamonas Obesus Levy et al [73,74] showed a reduction in ABC G5/G8 in the intestine. In the intestine of human subjects with type 2 diabetes, ABCG5 and G8 mRNA were both significantly lower compared to controls [71].…”

“…In the Sammomas Obesus model of type 2 diabetes, the animals exhibiting weight gain, hyperinsulinaemia and hypercholesterolaemia, NPC1-L1 protein and gene expression were both significantly reduced in the intestine and the authors found a lower capacity to absorb cholesterol compared to controls [73,]. This may suggest interspecies variation but it is a surprising finding considering that this animal model of diabetes has been shown to have increased production of intestinal lipoprotein-containing apo B48 [74]. The mechanism whereby the body is almost completely unable to absorb plant sterols was a mystery until recently.…”