Julie Etienne's thesis defence ( DO-IT team)- 27 june

Summary of the thesis:
Intestinal absorption of dietary fatty acids is a key step in cardio-metabolic health. However, the molecular mechanisms underlying fatty acids uptake by the absorptive cells of the intestine, the enterocytes, remain incompletely understood. This thesis proposes a quantitative, mechanistic modeling approach for the first steps of intestinal long-chain fatty acids absorption. The first chapter reviews the published quantitative data regarding long chain-fatty acids intestinal uptake, transport to the endoplasmic reticulum and re-esterification into triglycerides, as well as published mathematical models that address related questions. The second chapter is the core of the thesis. It proposes a quantitative and mechanistic model of the intestinal uptake of long chain-fatty acids, taking into account their hydrophobicity and their sensitivity to pH. This system of ordinary differential equations is composed of passive diffusion and of different modules (active transport, fatty acid-binding proteins (FABPs), intracellular metabolism), that were removed in turn to simulate gene knockouts. To allow for the quantitative comparison of uptake rates, a standardized dataset of long-chain fatty acid uptake rates was built based on nine published experimental datasets, originally expressed in various units. The simulations show that intracellular metabolism, acting as a sink for passive diffusion through the membrane, is critical to ensure total absorption of the dietary content, at the time scale of several hours. Removing FABP does not prevent total absorption, but delays the process by more than a hundred hours. The presence of active transport does not impact the long-term uptake dynamics, but is required to properly fit experimental data at the time scale of a few seconds or minutes. Beyond goodness-of-fit, dissecting the quantitative contribution of each subflux shows that two kinds of dynamics can underly a good fit. In the “physiological” dynamics, fatty acids enter the cell via passive diffusion and active transport and end up metabolized. In the “anomalous” dynamics, fatty acids enter via active transport, but most of them leave via outward passive diffusion instead of being metabolized. The third chapter describes the preliminary studies conducted to model the subsequent step of fatty acid re-esterification into triglycerides through the 2-monoglyceride pathway, which is generally considered the main pathway in enterocytes. Equations for bisubstrate enzyme kinetics and experimental data are studied. Altogether these results pave the way towards a numerical mirror of the enterocyte for long-chain fatty acids absorption.