Assembly and secretion of triglyceride-rich lipoproteins in the liver (very-low-density lipoproteins [VLDL]) and intestine (chylomicrons) are essential processes required for interorgan nutrient transport and whole-body energy metabolism. Over many decades, intensive research into the multifaceted regulation of hepatic VLDL assembly and secretion has contributed to a sophisticated understanding of the molecular mechanisms governing VLDL secretion (1). In contrast, there is increasing appreciation that intestinal lipoprotein assembly and secretion is not simply determined by fat ingestion (2) but is also regulated by the integration of signals from a multitude of systemic and paracrine factors (3,4). Furthermore, dysregulation of VLDL secretion in insulin-resistant states and diabetes has been well described for several decades, whereas dysregulation of chylomicron secretion in insulin resistance and diabetes has only more recently been appreciated (5,–,7). The observation that intestinal remnant lipoproteins, derived from the intravascular lipolysis of chylomicrons, are elevated in people living with insulin resistance and diabetes, along with speculation that these cholesterol-rich remnants contribute to atherogenesis, have stimulated further evaluation of the mechanisms that influence this process and have driven the study of intrinsic molecular dysregulation of intestinal lipoproteins (8,9).
Ingested fats undergo hydrolysis by lipases in the proximal intestine, resulting in release of fatty acids and monoacylglycerols, which are absorbed by enterocytes, where they are reesterified (3). Assembly of these lipids upon an apolipoprotein B48 (apoB48) backbone in the endoplasmic reticulum and Golgi forms mature chylomicrons that are secreted into the lymphatic system, via which they are transported to the blood circulation (10). The transition from fasting to feeding places the gut in a constant transitionary state whereby the priority is to maintain the ability to efficiently and rapidly absorb >95% of lipids without the unnecessary expense of cellular resources (11). As such, lipid-poor apoB48 particles of VLDL size and smaller are secreted in fasting states, while postprandially, the triglyceride and cholesteryl ester contents greatly increase particle size with more modest increases in particle number (12). Substrate availability is indeed by far the primary determinant of chylomicron size, composition, and secretion rate, but we now appreciate that there is a complex interplay of systemic factors that also regulate the rate of intestinal lipid mobilization and chylomicron secretion, both in the fasted and postprandial states (3,4).
Free fatty acid (FFA) flux to the liver is an important driver of VLDL secretion (13,14). Turning our interest to the intestine a decade later, studies in animal models and humans demonstrated, to our initial surprise, a similar impact of elevated plasma FFA in stimulating the production of intestinally derived chylomicrons (15,16). These data suggested that chronic elevation of plasma FFA flux from peripheral tissues to liver and intestine, characteristic of insulin-resistant individuals and those living with type 2 diabetes, may contribute to the overproduction of intestinal lipoproteins observed in these conditions. Furthermore, studies in cell lines, primary cultured hepatocytes, animal models, and humans demonstrated a consistent acute suppression of VLDL secretion (17,–,19) by insulin and resistance to that suppression in insulin resistance (20), with in vivo studies confirming that this suppression was partly due to insulin’s potent suppression of plasma FFA (14) but also due to a direct hepatic effect. As an extension of the above findings, in people living with type 2 diabetes, the acute suppressive effect of insulin signaling on apoB48 secretion was absent, and production of triglyceride-rich apoB48 production was found to be elevated (21,22).
In this Classics in Diabetes article, we revisit a 2010 Diabetes article titled “Insulin Acutely Inhibits Intestinal Lipoprotein Secretion in Humans in Part by Suppressing Plasma Free Fatty Acids” by Pavlic et al. (23). The human study extended the observation that elevated FFA stimulated chylomicron production and examined the impact of acute hyperinsulinemia on intestinal and hepatic lipoprotein production. Lipoprotein production rates in humans were assessed in a constant fed state, with and without insulin-induced suppression of plasma FFA. This study demonstrated that insulin acutely suppresses intestinal lipoprotein production in humans partly via acute signaling and partly by suppressing plasma FFA, similar to its effect on the liver. This study confirmed the importance of substrate flux via blood circulation to the intestine and hormonal signaling on intestinal chylomicron secretion, analogous to hepatic VLDL secretion. It opened the door to investigation of other signals not previously appreciated to play a role in regulating chylomicron secretion.
In the past decade, we have gained a greater understanding of several hormonal and nutritional regulators of chylomicron secretion, including glucagon-like peptide 1 (GLP-1) (24,25), GLP-2 (26,–,28), and glucose (29,–,31). Several other important observations have emerged from this research, enhancing our understanding of intestinal lipoprotein secretion. First, we now understand that a considerable portion of the fat absorbed from a high-fat meal and reesterified in the enterocyte is retained in the intestine for many hours following the meal in cytosolic lipid droplets and other intracellular and extracellular intestinal compartments. During lipid absorption, the size and number of cytosolic lipid droplets increase and then decline over time, with several stimuli identified that can mobilize retained fat (subsequent meal, GLP-2, glucose, and neural stimuli), and the amount stored can be related to the composition of the diet (32) and hormonal signaling (33). Second, some of the retained and subsequently mobilized intestinal fat is in the form of fully formed chylomicrons. Third, we have also come to appreciate that intracellular and postassembly regulatory mechanisms play an important role in chylomicron secretion (34,35). Fourth, we speculate that secreted chylomicrons retained in the intestinal lamina propria and in lymphatics draining the intestine are not all rapidly transported via lymphatics to the blood circulation, with the rate of lymph transport being regulated (36,37). How these rather large chylomicron particles gain access to the lymphatic vessel has been demonstrated through enterocyte basolateral membrane disruption during active absorption (38) and the opening of “button-like” junctions of the intestinal lacteal capillary through modulation of cytoskeleton contractility and dynamic signaling (39,40). Interestingly, the loss of PlagL2 transcription factor in mice resulted in the accumulation of chylomicrons in the lamina propria that failed to enter the lacteal, which resulted in postnatal wasting owing to failure of fat absorption (41). Additionally, these cellular processes may be regulated not only intrinsically but also extrinsically through microbial products (42) and substrates, as deletion of CD36 in intestinal lymphatic endothelial cells was linked with lymph leakage, visceral adiposity, and glucose intolerance, suggesting a role for the lymphatic system in whole-body metabolism (43). The regulation of lymphatic pumping has been underappreciated as a critical aspect of chylomicron secretion rate. Lymphatics serve as both a passive conduit and as an active pump controlled by hormonal and neural inputs (44). As such, lymphatic pumping is an important regulator of chylomicron and dietary lipid appearance in the circulation (45,46). Considerable work remains to understand the signals that regulate chylomicron transport rate from enterocytes to the lymphatics and blood circulation as well as regulatory factors that influence active lymphatic pumping.
The mechanisms underlying postprandial lipemia and the role of intestinally derived lipoproteins and their remnants in the development of macrovascular complications in people living with insulin resistance and type 2 diabetes continue to be elucidated (47). Early characterization of intestinal fat absorption as being overwhelmingly regulated by dietary substrates has been confirmed but has been further refined as work from the last two decades sheds light on the complex interplay between dietary substrate, hormonal signaling and resistance, and neural networks in regulating intestinal lipoprotein metabolism. Through these strides, a greater understanding of the molecular regulation of chylomicron secretion, trafficking, and transit via the lymphatic system has revealed novel aspects of intestinal lipoprotein metabolism.
The classic 2010 Diabetes article by Pavlic et al. can be found at https://doi.org/10.2337/db09-1297.
For more information on Classics in Diabetes, please see https://doi.org/10.2337/dbi23-0016.
Article Information
Funding. G.L. holds the Drucker Family Chair in Diabetes Research, and E.M. holds a Heart and Stroke New Investigator Award.
Duality of Interest. G.L. consults for and has received speaking honoraria from Amgen Canada. No other potential conflicts of interest relevant to this article were reported.
