Nutrition Obesity & Risk of Thrombosis

Unité Mixte de Recherche  INSERM 1062 / INRA 1260 / AMU

Bioavailability, Lipids and Micronutrients

TEAM 1

Leader: Patrick BOREL

 

Identification and pathophysiological significance of membrane transporters of lipid micronutrients

Leader: Emmanuelle REBOUL

Blood and tissue levels of vitamins and lipid phytomicronutrients (LPM), ie lipid soluble vitamins, carotenoids and phytosterols, have repeatedly been beneficially associated with the incidence of various diseases (cancer, cardiovascular diseases, neurodegenerative diseases ...).

These associations, reinforced by numerous mechanistic studies of cellular and animal models, support the protective role of these vitamins and LPM in some of these pathologies. However, at the individual level, blood and tissue concentrations of these compounds or their metabolites are generally not correlated with their consumption. This is explained by the very high inter-individual variability of absorption, metabolism and catabolism of these compounds. The factors responsible of this interindividual variability are potentially very numerous.

Our goal is to determine which factors are essential to explain and to control this phenomenon. We study first, the interindividual variability in bioaccessibility, probably due to differences in the effectiveness of the digestive capacity of individuals (variability in chewing food, variability in the secretion of digestive juices, variability in amounts of secreted enzymes ...).

We also study the nutritional modulation of micronutrient transporters expression. Indeed, insofar as micronutrients absorption is supported by more or less specific transporters (see theme on the identification of vitamin transporters and LPM), we assume that the absorption of some of these compounds is retro-regulated by nutritional modulation of the expression of these transporters.

Finally, we study the potential modulation of the expression and / or activity of carriers by genetic polymorphisms in the gene promoters of these transporters. The results of our research will optimize the recommendations for vitamin and LPM involved in the nutritional prevention of some diseases, and regarding of genetic characteristics of individuals.

 

 

 

Blue: pathways we have already identified  (published).

Green: in preparation.

Orange: study in progress.

basolateral secretion

Hypothesis explaining the role of minor genetic variations (variations of a single base pair or "SNP") in the interindividual variability of absorption of vitamins and lipid phytomicronutrients.

 

This hypothesis assumes that genetic variants alter the activity or expression of proteins involved in the transport of vitamins and LPM in the enterocyte.

T1: putative apical transporter (eg. SR-BI).

T2: putative intracellular carrier (eg. L-FABP).

T3: putative basolateral transporter (eg. ABCA1).

 

Interindividual variability in absorption efficiency of lipid vitamins and phytomicronutriments, for example  beta-carotene.

beta carotene concentration in chylomicrons during postprandial period following the ingestion of a test meal providing 120 mg of beta-carotene. The arrows represent the times at which  the test meals were given. The first brought beta carotene. The second did not provide beta-carotene.  The green curve represents the average of the concentrations measured in 16 healthy subjects. The blue curve represents the response of the subject who answered most (area under the largest curve), the curve violet, that of the subject who answered the least.

 

Borel P, Grolier P, Mekki N, et al. Low and high responders to pharmacological doses of beta-carotene : proportion in the population, mechanisms involved and consequences on beta-carotene metabolism. J Lipid Res 1998 ; 39 : 2250-60.

 

Patrick BOREL, Team 1 leader, is now a member of the Editorial board of Molecular Nutrition & Food Research.

 

Blood and tissue levels of vitamins and lipid phytomicronutrients (LPM), ie lipid soluble vitamins, carotenoids and phytosterols, have repeatedly been beneficially associated with the incidence of various diseases (cancer, cardiovascular diseases, neurodegenerative diseases ...).

These associations, reinforced by numerous mechanistic studies of cellular and animal models, support the protective role of these vitamins and LPM in some of these pathologies. However, at the individual level, blood and tissue concentrations of these compounds or their metabolites are generally not correlated with their consumption. This is explained by the very high inter-individual variability of absorption, metabolism and catabolism of these compounds. The factors responsible of this interindividual variability are potentially very numerous.

Our goal is to determine which factors are essential to explain and to control this phenomenon. We study first, the interindividual variability in bioaccessibility, probably due to differences in the effectiveness of the digestive capacity of individuals (variability in chewing food, variability in the secretion of digestive juices, variability in amounts of secreted enzymes ...).

We also study the nutritional modulation of micronutrient transporters expression. Indeed, insofar as micronutrients absorption is supported by more or less specific transporters (see theme on the identification of vitamin transporters and LPM), we assume that the absorption of some of these compounds is retro-regulated by nutritional modulation of the expression of these transporters.

Finally, we study the potential modulation of the expression and / or activity of carriers by genetic polymorphisms in the gene promoters of these transporters. The results of our research will optimize the recommendations for vitamin and LPM involved in the nutritional prevention of some diseases, and regarding of genetic characteristics of individuals.

 

 

 

Factors involved in the inter-individual variability of absorption of vitamins and lipid phytomicronutrients

Leader: Patrick BOREL

 

Carrier properly expressed: optimal efficiency.

A genetic variant has partially affected the expression or activity of the transporter.

A genetic variant has strongly affected the expression or activity of the transporter.

It is assumed that when all transporters are properly expressed and effective, the subjects are "good responders" for vitamins and LPM carried by these transporters. Conversely, when one or more transporters have their expression or activity strongly affected by genetic variants, the subjects are "low responders". Finally, when some carriers are less expressed or less effective, while others are perfectly expressed and effective, the subjects are "intermediate responders".

Role of enterocyte in lipid abnormalities during insulin resistance and their consequences on vitamins and lipid phytomicronutrients metabolism.

Leader: René VALERO

The increase in cardiovascular morbidity and mortality associated with insulin resistance (obesity, metabolic syndrome, type 2 diabetes) is a major public health problem. In insulin-resistant patients, dyslipidemia, characterized by a postprandial hyperlipidemia with excess triglyceride-rich lipoproteins (TRL), is a major cardiovascular risk factor.

Our group is interested in intestinal TRL overproduction, also called chylomicrons (apolipoprotein B48 is the specific marker), as a newly recognized component of insulin resistance. Our working hypothesis is that enterocyte insulin resistance and chylomicrons overproduction in hyperinsulinemia / insulin resistance states are key players in the mechanisms leading to pathophysiology of dyslipidemia. Numerous studies demonstrate that the gut is a metabolically active organ, receiving information from the periphery and able of modulating its synthesis and its function in lipid secretion substrates, hormones or other endogenous or exogenous substances. Our goal is to study the regulation of TRL of intestinal origin metabolism and to evaluate the impact of this disruption on lipid metabolism, but also on lipid soluble vitamins (A, E, D, K ) and lipid phytomicronutrients status(carotenoids and phytosterols) in various pathophysiological contexts in insulin-resistant patients.

The atherogenic potential of TRL necessitates the understanding of their intestinal overproduction and their plasma accumulation in insulin resistance syndromes. We aim to develop new treatments targeted on enterocyte to improve the lipid profile and vitamins and lipid phytomicroconstituants status of these patients, and reduce the incidence of cardiovascular diseases.

 

 

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Overproduction of intestinal TRL

Overproduction mechanisms in intestinal triglycerides rich lipoparticles  (TRL, chylomicrons) in a context of hyperinsulinemia / insulin resistance

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