Molecular processes that handle -- and mishandle -- dietary lipids

Abstract

Overconsumption of lipid-rich diets, in conjunction with physical inactivity, disables and kills staggering numbers of people worldwide. Recent advances in our molecular understanding of cholesterol and triglyceride transport from the small intestine to the rest of the body provide a detailed picture of the fed/fasted and active/sedentary states. Key surprises include the unexpected nature of many pivotal molecular mediators, as well as their dysregulation - but possible reversibility - in obesity, diabetes, inactivity, and related conditions. These mechanistic insights provide new opportunities to correct dyslipoproteinemia, accelerated atherosclerosis, insulin resistance, and other deadly sequelae of overnutrition and underexertion.

Figure 1. Overview of lipid transport from gut lumen to periphery to liver.

Detergents in hepatic bile, chiefly phospholipids (PL) and bile acids, emulsify lipids from food to form microscopic micelles within the gut lumen. Hepatic bile also contributes significant amounts of UC to these micelles. The pancreas secretes lipases that digest dietary lipids into chemical forms that can be absorbed by the gut epithelium, e.g., NEFAs, monoacylglycerides, and UC. Absorption of fatty acids and monoacylglycerides approaches 100% efficiency and occurs via passive diffusion and carrier-mediated processes (64). Cholesterol absorption averages about 50% efficiency with considerable interindividual variation. Enterocytes reesterify these lipids intracellularly and then package them into large particles, CMs, that are rich in triglycerides (TG) but also contain substantial amounts of UC and cholesteryl esters. These particles are secreted into thoracic lymph, which drains directly into the systemic bloodstream, bypassing the liver. The mixed lipid composition of CMs leads to a 2-step clearance process. First, when these particles reach the capillary beds of peripheral tissues, a key metabolic branch point occurs between energy storage in adipose tissue (blue arrows) and lipid combustion in striated muscle (green arrows). In a regulated fashion, CMs dock on the microvascular endothelium of these tissues, where LpL hydrolyzes CM triglycerides into NEFAs to deliver lipid calories for local use. In the second step of clearance, residual triglyceride-depleted, cholesteryl ester–rich particles, now called CM remnant lipoproteins, are released back into plasma. Under normal circumstances, the liver rapidly and safely removes them from the circulation (red arrows).

Figure 2. Processing of dietary lipid by the enterocyte: absorption, selection, packaging, and secretion.

In the apoB-dependent pathway (black arrows), apoB₄₈ becomes assembled in the ER with initially small amounts of triglycerides that are synthesized mainly by DGAT2 and transferred via MTP. UC imported from the gut lumen into the enterocyte via NPC1L1 and possibly other proteins becomes esterified by ACAT2 and also packaged into the newly forming apoB₄₈ lipoprotein. Continued lipidation in the ER inflates the particle, requiring stabilization of its surface by phospholipids and apoA-IV. The nascent particles are then transferred to the Golgi apparatus in noncanonical transport vesicles, further lipidated, and finally secreted as CMs into lymph. Some of the absorbed cholesterol and essentially all of the dietary noncholesterol sterols are pumped out of the enterocyte, back into the intestinal lumen for elimination from the body (blue arrows). In the apoB-independent pathway (green arrows), UC is absorbed into the enterocyte, and then ABCA1 facilitates its efflux from the plasma membrane onto extracellular apoA-I molecules. Movement onto preexisting extracellular HDL also occurs. The apoA-I originates both from local intestinal synthesis and from plasma. Absorption of NEFAs, monoglycerides, and lipid micronutrients across the brush border and esterification by acyl-CoA:monoacylglycerol acyltransferase enzymes are not shown here. CE, cholesteryl ester; PC, phosphatidylcholine; Sito, sitosterol and other noncholesterol sterols.

Figure 3. Integrated model of CM binding and hydrolysis on peripheral capillary endothelium.

Adipose tissue and striated muscle each synthesize LpL, regulated by the fasted/fed and active/sedentary metabolic states. HSPGs on the surfaces of these cells capture and internalize LpL for degradation. LpL that escapes degradation will be picked up by HSPGs and VLDL receptors on the basal surface of overlying endothelial cells for transcytosis to the luminal surface of capillaries (orange arrows). Heparan sulfate side-chains of syndecan and glypican are denoted by chains of small spheres. The major HSPGs of endothelium, syndecans and glypicans, move into detergent-insoluble membrane microdomains (rafts) rich in caveolin-1 (CAV1) upon clustering. On the apical surface, they encounter GPIHBP1, which should also move into rafts upon clustering. The highly negatively charged N-terminal domain of GPIHBP1 binds LpL with approximately 10-fold greater affinity than do endothelial HSPGs. Thus, after transcytosis, LpL should be torn away from syndecans and glypicans onto GPIHBP1 (pink arrows). Dimers of GPIHBP1 bind LpL and CMs, thereby providing a platform for CM docking and triglyceride lipolysis. These processes are facilitated by apoC-II and apoA-V. Lipolysis generates NEFAs that are transported by another raft molecule, CD36, across the endothelium and into adipocytes for energy storage (blue arrows) or into striated myocytes for combustion (green arrows). After hydrolysis of CM triglycerides, the endothelium releases apoB₄₈ remnant lipoproteins that are rich in LpL, apoE, and cholesteryl ester back into the circulation (red arrow). Under normal circumstances, these remnant particles undergo safe, swift uptake by the liver.

Figure 4. Efficient hepatic uptake of CM remnant lipoproteins.

Hepatic HSPGs exhibit extreme structural features of their carbohydrate side-chains that enhance ligand binding. Thus, HSPGs in the liver rapidly pull apoB₄₈ remnant lipoproteins out of plasma via interactions with positively charged proteins on the particles, chiefly LpL and apoE. Once in the liver, the particles encounter hepatic lipase (HL), which serves as an additional bridging molecule between HSPGs and lipoproteins. Shown are 2 pathways for particle clearance. The first is direct receptor-mediated uptake, in which cholesteryl ester–rich apoB₄₈ remnant lipoproteins pass from the hepatic sinusoid through the fenestrated endothelium and then bind directly to integral plasma membrane receptors (red arrows; shown are the LDL receptor, which binds apoE, and the syndecan and glypican HSPGs, which bind LpL, hepatic lipase, and apoE). The second clearance mechanism is a cooperative pathway, in which apoB₄₈ remnant lipoproteins from the hepatic sinusoid are first sequestered by matrix HSPGs within the space of Disse and then taken up in cooperation with the integral plasma membrane receptors (blue arrows; shown are the collagen XVIII and perlecan HSPGs). Also shown is one of several secreted enzymes (Enz), such as heparanase or the heparan 6-O-endosulfatases, that are expressed by liver, degrade HSPGs, and may dampen these processes.