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New Insights into the Regulation of Chylomicron Production Satya Dash,1,2 Changting Xiao,1,2 Cecilia Morgantini,1,2 and Gary F. Lewis1,2 1

Departments of Medicine and Physiology and the Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, M5G 2C4 Canada; email: [email protected]

2

Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, M5G 2C4 Canada

Annu. Rev. Nutr. 2015. 35:6.1–6.30

Keywords

The Annual Review of Nutrition is online at nutr.annualreviews.org

chylomicron, apolipoprotein B-48, triglyceride-rich lipoprotein, diabetic dyslipidemia, atherosclerosis

This article’s doi: 10.1146/annurev-nutr-071714-034338 c 2015 by Annual Reviews. Copyright  All rights reserved

Abstract Dietary lipids are efficiently absorbed by the small intestine, incorporated into triglyceride-rich lipoproteins (chylomicrons), and transported in the circulation to various tissues. Intestinal lipid absorption and mobilization and chylomicron synthesis and secretion are highly regulated processes. Elevated chylomicron production rate contributes to the dyslipidemia seen in common metabolic disorders such as insulin-resistant states and type 2 diabetes and likely increases the risk for atherosclerosis seen in these conditions. An in-depth understanding of the regulation of chylomicron production may provide leads for the development of drugs that could be of therapeutic utility in the prevention of dyslipidemia and atherosclerosis. Chylomicron secretion is subject to regulation by various factors, including diet, body weight, genetic variants, hormones, nutraceuticals, medications, and emerging interventions such as bariatric surgical procedures. In this review we discuss the regulation of chylomicron production, mechanisms that underlie chylomicron dysregulation, and potential avenues for future research.

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Contents

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1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 2. OVERVIEW OF DIETARY LIPID ABSORPTION AND CHYLOMICRON ASSEMBLY, SECRETION, AND CLEARANCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 2.1. Absorption of Dietary Triglyceride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 2.2. Cholesterol Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4 2.3. Triglyceride Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6 2.4. Chylomicron Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6 2.5. Chylomicron Clearance from the Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7 3. REGULATION OF CHYLOMICRON PRODUCTION . . . . . . . . . . . . . . . . . . . . . . . 6.8 3.1. Nutritional Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.8 3.2. Hormonal, Local, and Circulating Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.11 3.3. Pharmacological Agents, Nutraceuticals, and Other Treatments . . . . . . . . . . . . . . 6.13 3.4. Circadian Regulation of Chylomicron Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.15 4. THE GUT AS A LIPID STORAGE ORGAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.16 5. PLASMA CHYLOMICRON CONCENTRATION IN INSULIN RESISTANCE AND TYPE 2 DIABETES AND ITS POTENTIAL ROLE IN ATHEROSCLEROSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.17 5.1. Chylomicrons in Insulin Resistance and Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . 6.17 5.2. Chylomicrons and Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.17 6. GENETIC CONDITIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.18 6.1. Monogenic Conditions with Increased Circulating Chylomicrons . . . . . . . . . . . . . 6.18 6.2. Common Genetic Variants Associated with Increased Plasma Triglycerides . . . 6.19 6.3. Monogenic Causes of Hypotriglyceridemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.19 7. FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20 7.1. Gut Microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20 7.2. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20 7.3. Neural Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20 7.4. The Physiological Role and Regulation of Enteral Lipid Storage . . . . . . . . . . . . . . 6.20 8. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.20

1. INTRODUCTION Ingested triglyceride (TG) is hydrolyzed in the proximal intestinal lumen by lipases to produce fatty acids and monoacylglycerols (MAGs). These products are subsequently absorbed across the brush border of enterocytes, where they are reesterified to diacylglycerides (DAGs) and TGs (116). TGs are conjugated with apolipoprotein B48 in the enterocyte endoplasmic reticulum and Golgi to form chylomicrons, which are released into the circulation via the lymphatic system (130, 173). In the fasted state enterocytes secrete smaller, lipid-poor chylomicron particles. Postprandially, there is a relatively small increase in the number of chylomicron particles secreted, with a very large increase in the TG and cholesteryl ester content per particle, which greatly enlarges particle size (59). Although the major determinant of chylomicron production is dietary fat ingestion, a relatively underappreciated aspect of chylomicron production is that it is a highly regulated process, with paracrine and systemic factors affecting production rates beyond fat ingestion (173). Furthermore, although digestion, absorption, and incorporation of dietary fat into chylomicrons is a highly

TG: triglyceride

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efficient and rapid process, the gut is capable of storing dietary lipid in the cytosol of enterocytes and possibly the lacteals for several hours and subsequently mobilizing and releasing this stored lipid as chylomicrons many hours after a meal in response to various stimuli (22, 30, 44, 130). Here we provide an overview of the incorporation of dietary fat into chylomicrons and their subsequent release into the circulation. In addition, we review recent data from animal and human studies, identifying regulators of chylomicron production as well as factors affecting storage and subsequent release of enteral lipids. We also discuss conditions and disease states such as insulin resistance and type 2 diabetes, in which increased chylomicron production contributes to the typical dyslipidemia of these conditions and potentially accelerates atherosclerotic cardiovascular disease. Finally, we provide a summary of our current knowledge and future directions for research in the field.

FABPpm: fatty acid–binding protein plasma membrane FATP4: fatty acid transport protein 4 CD36: cluster determinant 36 I-FABP: intestinal fatty acid–binding protein

2. OVERVIEW OF DIETARY LIPID ABSORPTION AND CHYLOMICRON ASSEMBLY, SECRETION, AND CLEARANCE 2.1. Absorption of Dietary Triglyceride Dietary TG is solubilized in the duodenum and proximal jejunum by the action of bile acid micelles and is digested by lingual, gastric, and pancreatic lipases to yield monoacylglycerol and fatty acid, which are absorbed by the enterocytes in the small intestine (Figure 1). The absorption of fatty acid and monoacylglycerol is highly efficient, with absorption of more than 95% of ingested dietary lipid in vivo (116). Although absorption of monoacylglycerol and fatty acid likely occurs by passive diffusion across a concentration gradient, various transporters may promote enterocyte uptake of luminal long-chain fatty acid (LCFA) and serve important signaling functions. In vitro studies have implicated the fatty acid–binding protein plasma membrane (FABPpm) (149) and fatty acid–transport protein 4 (FATP4) (146), and in vivo studies have implicated fatty acid translocase/cluster determinant 36 (FAT/CD36) (106) (Figure 2). In addition, the plasma membrane protein caveolin can facilitate fatty acid absorption both in vitro and in vivo, potentially by interacting with CD36 (116, 129, 140). However, the presence of these fatty acid transporters is not absolutely necessary for luminal LCFA absorption. Treatment of jejunal explants with FABPpm antisera only modestly reduces LCFA uptake (149). FATP4 knockdown reduces fatty acid uptake by freshly isolated enterocytes in vitro (146), a finding replicated in enterocytes isolated from heterozygous FATP4 knockout mice (49). Furthermore, there is no evidence of fat malabsorption in mice treated with FATP4 inhibitors (10) or in heterozygous FATP4 knockout mice (homozygosity for FATP4 is embryonically lethal) (49). In CD36 knockout mice, lipid absorption in the proximal intestine is impaired (105). No major lipid malabsorption phenotype is seen, however, likely due to CD36-independent compensatory mechanisms in the distal gut (105). Similarly, in CD36-deficient humans, there is no evidence of lipid malabsorption (92). To date no specific transporters have been identified for monoacylglycerol. Within the enterocyte, cytoplasmic fatty acid–binding proteins (FABPcs) participate in intracellular transport of LCFAs (Figure 2). FABP-2 [intestine-specific FABP (I-FABP)] is expressed in the small intestine, associates with apical LCFA in a 1:1 ratio, and is thought to deliver these LCFAs to intracellular membranes such as the ER by a direct collision interaction to initiate TG synthesis in vitro (109). A human genetic variant in FABP-2, in which an alanine at codon 54 is substituted by a threonine, is associated with increased plasma TG (2), insulin resistance (7), and weight gain (62). This may be due to enhanced affinity for LCFA (7). However, FABP-2 knockout mice demonstrate no lipid malabsorption, which suggests that this protein is not essential for intestinal lipid absorption. Indeed, male FABP-2 knockout mice have higher body weights and www.annualreviews.org • Regulation of Chylomicron Production

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Glycerol phosphate pathway Dietary glucose

Glucose

sn Glycerol-3-phosphate GPAT 3, 4 FA CoA Lysophosphatidic acid

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Fatty acid

Fatty acid

FATP4

AGPAT 1–5

FA CoA

Phosphatidate Dietary lipid

Lipolysis

+

LIPIN 1–3

FA CoA Monoacylglycerol

Monoacylglycerol

MGAT

Diacylglycerol DGAT 1, 2

Monoacylglycerol phosphate pathway

FA CoA

Triacylglycerol

Figure 1 Triglyceride synthesis in the enterocyte. The monoacylglycerol pathway: This pathway contributes to approximately 75–80% of triglyceride synthesis within enterocytes, with the rest coming from the glycerol phosphate pathway. Dietary triglyceride is hydrolyzed to fatty acid and monoacylglycerol, both of which are absorbed across the intestinal brush border membrane. Fatty acid is converted to fatty acyl CoA by FATP4. Fatty acyl CoA and monoacylglycerol can be converted to diacylglycerol, catalyzed by the enzyme MGAT, which can be further converted to triacylglycerol by the enzyme DGAT. Glycerol phosphate pathway: Triacylglycerol can also be synthesized from glucose and fatty acyl CoA. sn Glycerol-3-phosphate, generated by glucose, is sequentially converted to lysophosphatidic acid, phosphatidate, and diacylglycerol by the addition of fatty acyl CoA catalyzed by GPAT, AGPAT, and lipin, respectively. Diacylglycerol is converted to triacylglycerol as described above. Abbreviations: AGPAT, 1-acyl-sn-glycerol-3-phosphate acyltransferase; CoA, coenzyme A; DGAT, diacylglycerol acyltransferase; FA, fatty acid; FATP4, fatty acid–transport protein 4; GPAT, glycerol-3-phosphate:acyl-CoA acyltransferase; MGAT, monoacylglycerol acyltransferase. Figure adapted with permission from Pan & Hussain 2012. Biochim. Biophys. Acta 1821:727–35 (116).

plasma TG concentrations (158). FABP-1 [liver-specific FABP (L-FABP)] is expressed in the liver, small intestine, and kidney (109). Each FABP-1 protein interacts with two LCFAs and transports them by aqueous diffusion in vitro. FABP-1 interacts with plasma membrane proteins and has been proposed to act as a cytoplasmic reservoir for fatty acid assimilation (109) and transport of nascent chylomicrons from the ER to the golgi in the form of prechylomicron transfer vesicle (PCTV) (107) in vitro. FABP-1 knockout mice have increased TG retention within enterocytes, with reduced TG secretion, and are protected against diet-induced obesity (108). L-FABP: liver fatty acid–binding protein PCTV: prechylomicron transport vesicle

2.2. Cholesterol Absorption Dietary cholesterol ester is hydrolyzed to free cholesterol and fatty acid, with absorption of fatty acid as described above in Section 1.1. Free cholesterol absorption and delivery to the ER are facilitated by the Niemann-Pick C1-like 1 receptor in vitro, a target of the cholesterol absorption inhibitor therapeutic agent ezetimibe (3, 134) (Figure 2). Free and reesterified (esterified by acyl CoA:cholesterol acyl transferase enzyme 2) cholesterol is transferred to nascent apolipoprotein

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Free fatty acids

Cholesterol

Diffusion FATP4 FABpm CD36

Cholesterol efflux

SR-B1 NPC1L1

ABCG5 ABCG8 Brush border membrane

FA I-FABP L-FABP

FC

ACAT2

FA

Endoplasmic reticulum

TG

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TG CE

TG

B48

MTP B48

MTP

apoAI

CMpri

B48 TG

CE B48 TG

Budding (L-FABP)

CMpre

A4

CE

Golgi

A4

CMpre

CE B48 TG

Fusion (Sar1b, SNARE)

A4

Sar1b

PCTV

VAMP7 CE B48 TG

Basolateral membrane

ABCA1 apoAI

Lymph HDL CE B48 TG

Figure 2 Chylomicron assembly and secretion. Free fatty acids are transported across the brush border membrane (BBM)—mainly by passive diffusion and to a lesser extent by fatty acid transporters (CD36, FATP4, and FABPpm)—and then to the endoplasmic reticulum (ER) by intracellular fatty acyl CoA transporters I-FABP (FABP-2) and L-FABP (FABP-1), where free fatty acid is resynthesized into triacylglycerol as described in Figure 1. Dietary cholesterol is transported across the BBM by the cholesterol transporters NiemannPick C1-like 1 (NPC1L1) and SR-B1. Free cholesterol can either be exported back to the lumen by ABCG5/8 or converted to cholesteryl ester (CE) and transported to the ER by ACAT2. In the ER, newly synthesized ApoB-48 is lipidated with triglyceride (TG), CE, and phospholipid by microsomal triglyceride transfer protein (MTP) to form a primordial chylomicron (CMpri ). Further addition of TG and cholesterol by MTP to the core of the primordial chylomicron generates a prechylomicron (CMpre ), which also acquires apoA IV. The prechylomicron is exported in a prechylomicron transport vesicle (PCTV) by budding from the ER aided by L-FABP. The PCTV fuses with the cis-Golgi aided by secretion-associated, Ras-related GTPase 1B (Sar1b) and soluble N-ethyl maleimide sensitive-factor attachment protein receptor (SNARE) proteins. In the Golgi, the prechylomicron acquires ApoA1. Mature chylomicrons are exported from the Golgi in vesicles and released into the basolateral surface of the enterocyte into the lymphatic circulation. Cholesterol can also be secreted into the basolateral membrane (BLM), independent of ApoB-48, along with ApoA1 as a high-density lipoprotein particle by the transporter ABCA1. Abbreviations: ABCA1, ATP–binding cassette transporter A1; ABCG5/8, ATP-binding cassette transporter G5/G8; ACAT2, acyl CoA:cholesterol acyltransferase enzyme 2; CD36, cluster determinant 36; FABPpm, fatty acid–binding protein plasma membrane; FATP4, fatty acid–transport protein 4; HDL, high-density lipoprotein; I-FABP, intestinal fatty acid–binding protein; L-FABP, liver fatty acid–binding protein; VAMP7, vesicle-associated membrane protein 7. Figure adapted with permission from Pan & Hussain 2012. Biochim. Biophys. Acta 1821:727–35 (116). www.annualreviews.org • Regulation of Chylomicron Production

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ApoB-48: apolipoprotein B-48 MTP: microsomal triglyceride transfer protein

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ABCA1: ATP-binding cassette transporter G5/G8 ABCG5/8: ATP-binding cassette transporter A1 MGAT: monoacylglycerol acyltransferase

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B-48 (ApoB-48) lipoprotein under the influence of microsomal triglyceride transfer protein (MTP) in vitro and in vivo (73) (see Section 2.4 and Figure 2) and eventually secreted as part of a chylomicron. Free cholesterol can also be secreted along with ApoA1 as a nascent high-density lipoprotein (HDL) particle under the influence of the ATP-binding cassette transporter G5/G8 (ABCA1) (16, 116) in vivo (Figure 2). In addition to secreting cholesterol into the circulation, the enterocyte can export cholesterol back into the lumen through two ATP-binding cassette transporters that are thought to function as heterodimers: ABCG5 and ABCG8 (60) (Figure 2). These two transporters are also important in ensuring that plant sterols are not absorbed. Loss-of-function mutations in either transporter in humans leads to sitosterolemia, characterized by an accumulation of plant sterols, tendon xanthomas in the presence of normal low-density lipoprotein (LDL) cholesterol, and premature coronary artery disease (60).

2.3. Triglyceride Synthesis Fatty acid entering the enterocyte is catalyzed by FATP4, which has acyl CoA synthetase activity, to fatty acyl CoA (99, 146) in vitro. In the ER of the enterocyte, dietary MAG and fatty acid CoA are covalently bonded to form DAG (Figure 1). This reaction is catalyzed by monoacylglycerol acyltransferase (MGAT) enzymes (91, 177) in vitro. MGAT2 is expressed in the small intestine of rodents and humans, whereas MGAT3 is expressed in the small intestine of humans only (23, 91). MGAT2 knockout mice have attenuated postprandial hypertriglyceridemia and resistance to diet-induced obesity (176). DAG is then further acylated by diacylglycerol acyltransferase (DGAT) enzymes (Figure 1). This is achieved by the enzymes DGAT1 and DGAT2 in rodents, whereas human small intestine expresses DGAT1 only (17, 21, 54, 148). Haas et al. (54) reported a family in which two siblings had a homozygous mutation in DGAT1, with near undetectable DGAT1 expression. These individuals presented with severe neonatal onset diarrhea, with one sibling passing away at the age of 17 months but with improvement in symptoms with time in the other sibling. DGAT1 inhibitors are currently being assessed for the treatment of hypertriglyceridemia, but their clinical development has been hampered by the side effect of diarrhea (33). The phenotype of DGAT1 deficiency in humans is more severe than that of DGAT1 knockout mice (which have normal but delayed fat absorption and resistance to diet-induced obesity), possibly due to the presence of DGAT2 in mice (17). MGAT3, expressed in the small intestine in humans, has DGAT activity in vitro (19, 91). It is estimated that approximately 75% of intestinal TG synthesis is carried out by the esterification of dietary MAG, with the majority being directed to chylomicron formation (116, 175) in vivo in rats. Enterocytes can also synthesize TG from glucose via the glycerophosphate pathway (Figure 1), although this is a relatively minor pathway in humans, accounting for less than 30% of enterocyte TG synthesis. This TG is primarily stored in the cytosol of enterocytes (116, 175).

DGAT: diacylglycerol acyltransferase

2.4. Chylomicron Synthesis ApoB-48 is the major, nonexchangeable apolipoprotein of chylomicrons. It is encoded by the APOB gene. Unlike the liver, which secretes the full-length ApoB-100 (4,536 amino acids), in the intestine ApoB is post-transcriptionally edited by Apobec-1, resulting in the insertion of a premature stop codon and generation of a truncated ApoB protein that is 48% of the length of ApoB-100 (ApoB-48; 2,152 amino acids) (5). In vitro studies have shown that in the absence of lipidation, ApoB-48 is degraded (100, 116). The enzyme MTP catalyzes the lipidation of ApoB-48 in the inner leaflet of the ER (Figure 2). It is a heterodimer of a 97-kDa catalytic subunit and protein disulfide isomerase. It catalyzes the addition of TG, cholesterol ester, and phospholipid to ApoB-48 to generate secretion-competent primordial chylomicrons in vitro. Unlike unlipidated ApoB-48, these 6.6

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primordial chylomicron particles can be stored in the apical aspect of the enterocytes, possibly in the ER (100, 116). In the fasted state, the enterocyte secretes relatively lipid-poor chylomicron particles (59). Under postprandial conditions, the primordial chylomicron particles are further lipidated with TG and cholesteryl ester to generate larger prechylomicron particles, which are transferred to the Golgi for maturation and secretion (91) (Figure 2). In addition to ApoB-48, chylomicrons have a number of exchangeable apolipoproteins. Apolipoprotein A-IV (ApoA-IV) is an exchangeable lipoprotein that is incorporated into chylomicrons at an early stage within the ER. It resides on the surface of chylomicrons and may be important for chylomicron synthesis and secretion. ApoA-IV overexpression in vitro increases TG packaging of chylomicrons in the ER with increases in MTP expression, although ApoA-IV overexpression in vivo is not associated with increased fat absorption or chylomicron production (1). ApoA-IV knockout mice have reduced MTP expression (117) but have no malabsorption of lipid or reduced chylomicron production (163). Prechylomicron particles synthesized in the ER are transported to the Golgi for further maturation. In vitro studies have shown that these relatively large particles are transported in PCTVs, which comprise COPII proteins, ApoB-48, CD36, and FABP-1 as well as vesicle-associated membrane protein 7 (VAMP7) (91, 141, 142) (Figure 2). FABP-1 is sufficient to initiate synthesis of PCTV and its budding from the ER. FABP-1 is part of a cytosolic protein complex (comprising Sar1b, Sec13, and small valosin-containing protein/p97-interactive protein) that prevents FABP-1 binding to the ER. Protein kinase C-zeta mediates phosphorylation of the Sar1b, in an ATPdependent manner, which disassembles the complex that permits binding of FABP-1 to the ER and generation and budding of the PCTV in vitro (139). The PCTV then fuses with the cis-Golgi by the interaction of VAMP7 with Golgi membrane proteins syntaxin 5, rbet1, and vit1a (91, 116, 141, 142). In the Golgi, the prechylomicron gains apoA-1, and ApoB-48 undergoes glycosylation. Chylomicrons are then transferred from the trans-Golgi to the basolateral membrane via vesicles, which exocytose the chylomicrons into the lamina propria and eventually into the circulation via the lymphatic system (116) (Figure 2).

VAMP7: vesicle-associated membrane protein 7

2.5. Chylomicron Clearance from the Circulation Once in the circulation, chylomicrons acquire further exchangeable apolipoproteins such as apoC2, apoC3, and apoE (26, 173). The TG component of the chylomicron is hydrolyzed by lipoprotein lipase (LPL) expressed on the surface of endothelial cells of the vasculature of adipose tissue, skeletal muscle, and myocardium. ApoC2 is a cofactor promoting LPL activity, whereas ApoC3 inhibits it (173). Loss-of-function mutations in LPL and ApoC2 in humans cause familial chylomicronemia with marked hypertriglyceridemia and increased risk of acute pancreatitis (15, 61). Conversely, loss-of-function mutations in apoC3 are associated with low plasma concentration of TGs and remnant particles and protection from atherosclerotic cardiovascular diseases (27, 79). Genetic mutations in humans have also revealed the physiological importance of lipase maturation factor 1 (encoded by LMF1), glycophosphatidylinositol HDL-binding protein-1 (encoded by GPHIB1), and ApoA5 (encoded by APOA5) in regulating chylomicron clearance (61). Lipase maturation factor 1 is an ER protein that posttranslationally activates LPL. Glycophosphatidylinositol HDL-binding protein-1 transfers LPL across and tethers it to the endothelial surface, whereas ApoA5 interacts with LPL to promote chylomicron hydrolysis (77). Hydrolysis of chylomicron TGs by LPL yields remnant particles that are potentially atherogenic (11, 89). These remnant particles are removed from the circulation by the liver. ApoE facilitates the binding of these remnants to the heparan sulphate proteoglycans on the surface of hepatocytes, which are then internalized by the action of the LDL receptor and LDL receptor-related protein 1 (69, 167). It is worth noting that TG-rich very-low-density lipoprotein (VLDL) particles produced www.annualreviews.org • Regulation of Chylomicron Production

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Diet

Genetic variants and disorders

Circadian regulation

Circulation factors

Chylomicron secretion

? Microbiota

Drugs and bariatric surgery

? Neural regulation

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Metabolic disorders

Figure 3 Summary of known and potential novel factors regulating chylomicron secretion. Question marks denote factors that potentially regulate chylomicron production and warrant further investigation.

by the liver are also removed by similar saturable mechanisms, with competition between VLDL and chylomicrons for removal. In summary, dietary lipid is digested, absorbed, incorporated into chylomicrons, and transported in the circulation before being cleared. This process involves a complex interaction between dietary lipid, transporters, lipoproteins, and enzymes.

3. REGULATION OF CHYLOMICRON PRODUCTION Although ingested fat is the major driver of chylomicron production, recent research has shown that chylomicron production is a highly regulated process and that other factors affect this process, including nonlipid nutritional factors, hormones and circulating factors, genetic variants, circadian rhythms, nutraceuticals, and therapeutic interventions (pharmacological agents as well as bariatric surgery) (61, 70, 114, 174) (Figure 3). These findings are important, as increased chylomicron production contributes to postprandial hypertriglyceridemia, an independent risk factor for atherosclerosis (8, 111, 174). In the postprandial state, there is a small increase in the number of chylomicron particles, but each particle is considerably larger, with increased lipid content (59). Following lipolysis, as described above (Section 2.5), these chylomicrons are converted to chylomicron remnant particles. In certain conditions such as insulin resistance and type 2 diabetes, circulating chylomicron and remnant particles increase; the latter are thought to be atherogenic (173). Reducing chylomicron production may therefore be a potential therapeutic target in reducing atherosclerotic risk in certain patient populations. In this section, we discuss some of the factors regulating chylomicron production. For many of the factors reported, kinetic studies assessing the production and clearance of chylomicrons have not been reported, and therefore studies assessing the impact of these factors on chylomicron or plasma TG concentrations are included in the following discussion.

3.1. Nutritional Factors 3.1.1. Lipids. Acute studies of the effects of lipids. In addition to the quantity of dietary lipid, the composition of ingested fat affects chylomicron concentration. Low doses of dietary fat (

New Insights into the Regulation of Chylomicron Production.

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