Role of the gut in lipid homeostasis

Abstract

Intestinal lipid transport plays a central role in fat homeostasis. Here we review the pathways regulating intestinal absorption and delivery of dietary and biliary lipid substrates, principally long-chain fatty acid, cholesterol, and other sterols. We discuss the regulation and functions of CD36 in fatty acid absorption, NPC1L1 in cholesterol absorption, as well as other lipid transporters including FATP4 and SRB1. We discuss the pathways of intestinal sterol efflux via ABCG5/G8 and ABCA1 as well as the role of the small intestine in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. We review the pathways and genetic regulation of chylomicron assembly, the role of dominant restriction points such as microsomal triglyceride transfer protein and apolipoprotein B, and the role of CD36, l-FABP, and other proteins in formation of the prechylomicron complex. We will summarize current concepts of regulated lipoprotein secretion (including HDL and chylomicron pathways) and include lessons learned from families with genetic mutations in dominant pathways (i.e., abetalipoproteinemia, chylomicron retention disease, and familial hypobetalipoproteinemia). Finally, we will provide an integrative view of intestinal lipid homeostasis through recent findings on the role of lipid flux and fatty acid signaling via diverse receptor pathways in regulating absorption and production of satiety factors.

FIGURE 1

Aspects of CD36 signaling and trafficking that may have potential relevance to the regulation of intestinal lipid metabolism. The figure proposes some hypothetical working concepts regarding steps that may be involved in the effect of intestinal CD36 to facilitate fatty acid (FA) uptake and chylomicron formation. A: CD36 is highly expressed on enterocytes of the proximal intestine and localizes to the apical side of intestinal villi (132, 155, 170) where it interacts with FA released from the digestion of dietary triglycerides. While CD36 functions in facilitating uptake of FA by proximal enterocytes (155, 183), it does not contribute quantitatively to FA absorption (47, 156), since it would be rapidly saturated at the levels of monomeric FA present in the lumen. However, CD36-mediated FA uptake and associated signaling, operating at the very early stages of absorption, may promote intracellular events that facilitate chylomicron assembly (46, 88, 156). CD36 signaling is in most cases initiated via the CD36-associated Src kinases and downstream via the extracellular regulated kinase ERK1/2 (109). This signaling pathway may be important for phosphorylating proteins required for coordinating ER processing of prechylomicron vesicles (PCTV). CD36 has also been identified in the protein complex that is required for formation of the PCTV (190). B: recent data indicate that CD36 signaling may also be mediated by a rise in intracellular calcium. Calcium release from the ER promotes membrane CD36 localization, which regulates calcium influx via the store-operated calcium channel. The sustained increase in intracellular calcium could influence multiple events related to lipid processing or secretion (16, 109). B also illustrates the concept that CD36 is downregulated by FA via ubiquitination and lysosomal degradation (196), and this feedback loop may work to reduce CD36 function in the presence of high concentrations of long-chain fatty acids (LCFA) (207). In the enterocytes, the LCFA-induced decrease in CD36 associates with reduced activation of ERK1/2 which may serve to upregulate MTTP abundance (138).

FIGURE 2

Pathways regulating intestinal sterol absorption and homeostasis. Dietary/biliary cholesterol and other sterols are transported across the brush border principally via NPC1L1, a 13-transmembrane domain protein (shown only schematically here) with a sterol-sensing domain, that functions possibly in association with CD36. Note that the figure illustrates a conformational change in NPC1L1 upon sterol binding. NPC1L1 is expressed in subapical domains but not within the brush-border membrane and undergoes clathrin-mediated internalization following sterol binding, after which the sterol cargo is vectorially delivered to the endoplasmic reticulum for esterification via acyl cholesterol acyltransferase-2 (ACAT2). NPC1L1 then recycles back in proximity to the brush border. Sitosterol and other sterols are less effective substrates for ACAT2 and are preferentially secreted back into the intestinal lumen through the paired half-transporters ABCG5/G8. A portion of cytoplasmic intestinal free cholesterol is also selectively secreted back into the lumen through ABCG5/G8. An alternative pathway has been proposed to account for the portion of intestinal cholesterol excretion that operates independently of ABCG5/G8, referred to as transintestinal cholesterol efflux (TICE). The transporters involved and the metabolic source of cholesterol are unknown. Other apical transporters have been described, including SR-B1 and CD-36, but the significance of these two transporters in absorption of cholesterol and other sterols is yet to be established. Intestinal cholesterol ester (CE) is partitioned into distinct metabolic pools, including a dominant apoB48-dependent chylomicron pathway (CM) that requires microsomal triglyceride transfer protein (MTTP). Cholesterol, in the form of cholesterol ester (CE), can also be secreted via apoA1-dependent pathways, although the quantitative importance of this pathway is unknown. The metabolic pool of free cholesterol (FC) arises through de novo synthesis, from receptor-dependent lipoprotein uptake and also through mobilization of membrane free cholesterol. These pathways are summarized schematically by the dashed arrow. Intracellular free cholesterol from any of these sources may also enter the metabolic pool from which ACAT2 derives its substrate. In addition, membrane free cholesterol may be mobilized, along with phospholipid, through the export pump ABCA1, resulting in transfer to an extracellular apoA-I acceptor with the formation of discoidal HDL particles that enter the lymphatic circulation.

FIGURE 3

Model of intestinal triglyceride-rich lipoprotein assembly. The nascent apoB polypeptide is cotranslationally translocated across the rough endoplasmic reticulum (ER) membrane (1). The membranes of the ER are shown in yellow. When lipid (triglyceride, TG) is available, physical interactions between the NH₂-terminal domain of apoB and the microsomal triglyceride transfer protein (MTTP) promote optimal folding and direct biogenesis of a primordial lipoprotein particle (1a). MTTP exists as a heterodimeric complex with the chaperone protein protein disulfide isomerase (PDI). MTTP also promotes mobilization of triglyceride-rich lipid droplets from the bilayer of the adjacent smooth ER into the lumen of the ER to become luminal lipid droplets (2). When lipid availability is limited or MTTP function is impaired, nascent apoB becomes misfolded (1b) and is degraded, either within the ER lumen via ER-associated degradation pathways (ERAD), or the misfolded protein undergoes ubiquitination and is degraded by the proteasomal pathway. During the second step of lipoprotein assembly, the primordial lipoprotein particle fuses with endoluminal lipid droplets, resulting in prechylomicron transport vesicle (PCTV) formation (3). Other proteins, including CD36 and L-Fabp, also participate in PCTV formation. After fusion with key vesicular transport proteins, including COP II proteins, the prechylomicron particles are incorporated into a vesicular complex that buds from the ER and fuses with Golgi membranes. Vectorial transport of these prechylomicron particles (4) results in their continued maturation and eventually secretion (5) of the mature, nascent chylomicron particles into the pericellular spaces adjacent to lymphatic fenestrae. The basolateral membrane (shown schematically with a mature chylomicron traversing into the lymphatic fenestrae) is illustrated in blue.

FIGURE 4

Signaling functions of LCFA. Dietary triglyceride hydrolysis during digestion releases LCFA that have important signaling functions at various levels of the digestive tract. In the oral cavity, LCFA receptors (CD36, GPR120) present on the apical surface of taste bud cells in the tongue (49, 102) contribute to fat taste perception which associates with secretion of neurotransmitters, signal transmission to brain centers, and induction of the early cephalic phase of digestion (102) (blue arrows). In the intestinal lumen, dietary lipids have satiety effects (green arrows) mediated by LCFA signaling to release peptides with inhibitory effects on food intake (GLP-1, CCK, OEA). GLP-1 and CCK also delay gastric emptying and lipid absorption (23). GLP-1 and GIP enhance insulin release from the pancreas and glucose metabolism (10). Lipid sensing in the proximal gut mediated by accumulation of long-chain fatty acyl-coenzyme A also activates an intestine-brain-liver axis to inhibit glucose production by the liver (194).