Sensing of Dietary Lipids by Enterocytes: A New Role for SR-BI/CLA-1

BACKGROUND: The intestine is responsible for absorbing dietary lipids and delivering them to the organism as triglyceride-rich lipoproteins (TRL). It is important to determine how this process is regulated in enterocytes, the absorptive cells of the intestine, as prolonged postprandial hypertriglyceridemia is a known risk factor for atherosclerosis. During the postprandial period, dietary lipids, mostly triglycerides (TG) hydrolyzed by pancreatic enzymes, are combined with bile products and reach the apical membrane of enterocytes as postprandial micelles (PPM). Our aim was to determine whether these micelles induce, in enterocytes, specific early cell signaling events that could control the processes leading to TRL secretion. METHODOLOGY/PRINCIPAL FINDINGS: The effects of supplying PPM to the apex of Caco-2/TC7 enterocytes were analyzed. Micelles devoid of TG hydrolysis products, like those present in the intestinal lumen in the interprandial period, were used as controls. The apical delivery of PPM specifically induced a number of cellular events that are not induced by interprandial micelles. These early events included the trafficking of apolipoprotein B, a structural component of TRL, from apical towards secretory domains, and the rapid, dose-dependent activation of ERK and p38MAPK. PPM supply induced the scavenger receptor SR-BI/CLA-1 to cluster at the apical brush border membrane and to move from non-raft to raft domains. Competition, inhibition or knockdown of SR-BI/CLA-1 impaired the PPM-dependent apoB trafficking and ERK activation. CONCLUSIONS/SIGNIFICANCE: These results are the first evidence that enterocytes specifically sense postprandial dietary lipid-containing micelles. SR-BI/CLA-1 is involved in this process and could be a target for further study with a view to modifying intestinal TRL secretion early in the control pathway

Lipid-dependent Bidirectional Traffic of Apolipoprotein B in Polarized Enterocytes

Enterocytes are highly polarized cells that transfer nutrients across the intestinal epithelium from the apical to the basolateral pole. Apolipoprotein B (apoB) is a secretory protein that plays a key role in the transepithelial transport of dietary fatty acids as triacylglycerol. The evaluation of the control of apoB traffic by lipids is therefore of particular interest. To get a dynamic insight into this process, we used the enterocytic Caco-2 cells cultured on microporous filters, a system in which the apical and basal compartments can be delimited. Combining biochemical and morphological approaches, our results showed that, besides their role in protection from degradation, lipids control the intracellular traffic of apoB in enterocytes. A supply of fatty acids and cholesterol is sufficient for the export of apoB from the endoplasmic reticulum and its post-Golgi traffic up to the apical brush-border domain, where it remains until an apical supply of complex lipid micelles signals its chase down to the basolateral secretory domain. This downward traffic of apoB involves a microtubule-dependent process. Our results demonstrate an enterocyte-specific bidirectional process for the lipid-dependent traffic of a secretory protein

Détection luminale des micelles lipidiques

Post-prandial hypertriglyceridemia is a risk factor for metabolic diseases. The intestine, through its role in alimentary lipid absorption, participates in the secretion of lipoprotein rich-triglycerides (TRL) and contributes to the increase in plasma triglyceride levels during the postprandial state. Understanding the molecular mechanisms involved in the secretion of intestinal TRL would allow the identification of new drug targets for treatment of metabolic diseases. The sensing of lipids by intestinal cells represents a promising mechanism allowing the modulation of TRL secretion. While many studies show the importance of enteroendocrine cells in the detection of alimentary lipids, several evidence suggest also the implication of enterocytes, the absorptive intestinal cells, in this process. Recent experimental results on the role of the scavenger receptor SR-BI in the detection of dietary lipids, supplied in their physiological form of postprandial lipid micelles, are reviewed

Détection luminale des micelles lipidiques

Post-prandial hypertriglyceridemia is a risk factor for metabolic diseases. The intestine, through its role in alimentary lipid absorption, participates in the secretion of lipoprotein rich-triglycerides (TRL) and contributes to the increase in plasma triglyceride levels during the postprandial state. Understanding the molecular mechanisms involved in the secretion of intestinal TRL would allow the identification of new drug targets for treatment of metabolic diseases. The sensing of lipids by intestinal cells represents a promising mechanism allowing the modulation of TRL secretion. While many studies show the importance of enteroendocrine cells in the detection of alimentary lipids, several evidence suggest also the implication of enterocytes, the absorptive intestinal cells, in this process. Recent experimental results on the role of the scavenger receptor SR-BI in the detection of dietary lipids, supplied in their physiological form of postprandial lipid micelles, are reviewed

Sensing of Dietary Lipids by Enterocytes: A New Role for SR-BI/CLA-1

Background: The intestine is responsible for absorbing dietary lipids and delivering them to the organism as triglyceriderich lipoproteins (TRL). It is important to determine how this process is regulated in enterocytes, the absorptive cells of the intestine, as prolonged postprandial hypertriglyceridemia is a known risk factor for atherosclerosis. During the postprandial period, dietary lipids, mostly triglycerides (TG) hydrolyzed by pancreatic enzymes, are combined with bile products and reach the apical membrane of enterocytes as postprandial micelles (PPM). Our aim was to determine whether these micelles induce, in enterocytes, specific early cell signaling events that could control the processes leading to TRL secretion. Methodology/Principal Findings: The effects of supplying PPM to the apex of Caco-2/TC7 enterocytes were analyzed. Micelles devoid of TG hydrolysis products, like those present in the intestinal lumen in the interprandial period, were used as controls. The apical delivery of PPM specifically induced a number of cellular events that are not induced by interprandial micelles. These early events included the trafficking of apolipoprotein B, a structural component of TRL, from apical towards secretory domains, and the rapid, dose-dependent activation of ERK and p38MAPK. PPM supply induced the scavenger receptor SR-BI/CLA-1 to cluster at the apical brush border membrane and to move from non-raft to raft domains. Competition, inhibition or knockdown of SR-BI/CLA-1 impaired the PPM-dependent apoB trafficking and ERK activation. Conclusions/Significance: These results are the first evidence that enterocytes specifically sense postprandial dietary lipidcontainin

Preferential association of Hepatitis C virus with apolipoprotein B48-containing lipoproteins.

Hepatitis C virus (HCV) in cell culture has a density comparable to that of other members of the family Flaviviridae, whereas in vivo infectious particles are found partially in low-density fractions, associated with triacylglycerol (TG)-rich lipoproteins (TRLs). In the blood of infected patients, HCV circulates as heterogeneous particles, among which are lipo-viroparticles (LVPs), globular particles rich in TG and containing viral capsid and RNA. The dual viral and lipoprotein nature of LVPs was addressed further with respect to apolipoprotein composition and post-prandial dynamic lipid changes. The TRLs exchangeable apoE, -CII and -CIII, but not the high-density lipoprotein apoA-II, were present on LVPs, as well as the viral envelope proteins. apoB100 and -B48, the two isoforms of the non-exchangeable apoB, were represented equally on LVPs, despite the fact that apoB48 was barely detectable in the plasma of these fasting patients. This indicates that a significant fraction of plasma HCV was associated with apoB48-containing LVPs. Furthermore, LVPs were enriched dramatically and rapidly in triglycerides after a fat meal. As apoB48 is synthesized exclusively by the intestine, these data highlight the preferential association of HCV with chylomicrons, the intestine-derived TRLs. These data raise the question of the contribution of the intestine to the viral load and suggest that the virus could take advantage of TRL assembly and secretion for its own production and of TRL fate to be delivered to the liver

Trafficking of apoB is specifically induced by alimentary lipid-containing micelles.

<p>Confocal image of apolipoprotein B (apoB, red channel) and sucrase-isomaltase (SI, used as a brush-border marker, green channel) localizations in differentiated Caco-2/TC7 cells cultured in the absence (control) or presence of postprandial (PPM) or inter-prandial (IPM) micelles added at the apical pole of the cells for 20 min. Top panels show XY acquisitions at the apical level and at 3 µm and 5 µm below the apical plane. Bottom panels show the corresponding XZ projections (zoom ×2). (bar, 20 µm).</p