Metabolic Fate of Chylomicron Phospholipids and Apoproteins in the Rat

Tall, Alan R.; Green, Peter H. R.; Glickman, Robert M.; Riley, Jeffrey B.

doi:10.1172/jci109564

Cited by 210 publications

(62 citation statements)

References 49 publications

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“…Plasma apoA-I levels in healthy humans increases after ingestion of a fatty meal (35). Moreover, apoA-I can be transferred from chylomicrons to HDL (36). Thus, in our Lpcat3 KO mice, the observed significant reduction in plasma apoA-I level is the major outcome of defective absorption of cholesterol, triglycerides, and phospholipids (Fig.…”

Section: Discussionmentioning

confidence: 71%

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Kabir

Bui

et al. 2016

Journal of Biological Chemistry

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Lysophosphatidylcholine acyltransferase 3 (Lpcat3) is involved in phosphatidylcholine remodeling in the small intestine and liver. We investigated lipid metabolism in inducible intestine-specific and liver-specific Lpcat3 gene knock-out mice. We produced Lpcat3-Flox/villin-Cre-ER T2 mice, which were treated with tamoxifen (at days 1, 3, 5, and 7), to delete Lpcat3 specifically in the small intestine. At day 9 after the treatment, we found that Lpcat3 deficiency in enterocytes significantly reduced polyunsaturated phosphatidylcholines in the enterocyte plasma membrane and reduced Niemann-Pick C1-like 1 (NPC1L1), CD36, ATP-binding cassette transporter 1 (ABCA1), and ABCG8 levels on the membrane, thus significantly reducing lipid absorption, cholesterol secretion through apoB-dependent and apoB-independent pathways, and plasma triglyceride, cholesterol, and phospholipid levels, as well as body weight. Moreover, Lpcat3 deficiency does not cause significant lipid accumulation in the small intestine. We also utilized adenovirus-associated virus-Cre to deplete Lpcat3 in the liver. We found that liver deficiency only reduces plasma triglyceride levels but not other lipid levels. Furthermore, there is no significant lipid accumulation in the liver. Importantly, small intestine Lpcat3 deficiency has a much bigger effect on plasma lipid levels than that of liver deficiency. Thus, inhibition of small intestine Lpcat3 might constitute a novel approach for treating hyperlipidemia.The majority of lipids on the cell membrane as well as the plasma lipoproteins are phospholipids, in particular phosphatidylcholines (PCs) 2 (1, 2). Monounsaturated and saturated fatty acids are usually esterified at the sn-1 position of PCs, whereas polyunsaturated fatty acids are esterified at the sn-2 position (3). The asymmetric distribution of fatty acids at the sn-1 and sn-2 positions of PCs is maintained in part by a deacylationreacylation process known as the Lands cycle or PC remodeling (3, 4). One key enzyme in this remodeling is lysophosphatidylcholine acyltransferase (Lpcat), which utilizes lyso-PC and polyunsaturated acyl-CoA to produce sn-2 polyunsaturated PCs. There are four isoforms of this enzyme (5), and Lpcat3 is the major isoform in the small intestine and liver (6 -8).Lpcat3 is one of the downstream targets of liver X receptor (8) and peroxisome proliferator-activated receptor ␣ (6). Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8). Moreover, global Lpcat3 knock-out (KO) mice exhibit neonatal lethality and have an abnormal small intestine (9, 10). Liver-specific deletion of Lpcat3 has no effect on ER stress but results in a reduction of plasma triglycerides and induction of hepatosteatosis under high fat feeding conditions (9). Because of neonatal lethality (non-inducible approach was utilized), only 1-week-old newborns were analyzed for the impact of intestine-specific Lpcat3 deficiency on lipid metabolism (9). Very recently, we found that...

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Section: Discussionmentioning

confidence: 71%

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Kabir

Bui

et al. 2016

Journal of Biological Chemistry

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“…3940 However, Forte et al 41 have shown that heparin-induced lipolysis of plasma from HTG subjects results in the accumulation (at d= 1.006 to 1.063 g/mL) of flattened, liposomelike vesicles and large spherical particles with lamellar structure on the surface. Tall et al 40 have shown that in vivo lipolysis of TG-rich lipoproteins in rats after an ir jection of a large dose of chylomicrons results in the appearance of liposome-like vesicles in blood. These in vivo data suggest that free lipolytic surface remnants and/or surface remnant-enriched remnants of TG-rich lipoproteins may exist under certain circumstances in circulating blood, eg, in dyslipidemic subjects or during the postprandial lipemic state.…”

Section: Discussionmentioning

confidence: 99%

Liposome-like particles isolated from human atherosclerotic plaques are structurally and compositionally similar to surface remnants of triglyceride-rich lipoproteins.

Chung¹,

Tallis²,

Yalamoori³

et al. 1994

Arterioscler Thromb

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Recent studies have demonstrated the presence of unesterified cholesterol-rich, liposome-like vesicles in the extracellular space of atherosclerotic lesions in humans and animals. Liposome-like vesicles accumulate in the subendothelial space in rabbits within 2 weeks of initiation of cholesterol feeding, well before foam cells appear. These observations suggest that extracellular liposome-like vesicles may play a pivotal role in atherogenesis. The origin of these particles is unknown. We report a combination of in vivo and in vitro experiments that suggest a novel origin for these liposome-like vesicles. We demonstrate that the liposome-like particles isolated from postmortem human atherosclerotic plaques are rich in intact apolipoprotein (apo) A-I, C apolipoproteins, and sphingomyelin. We show that the in vivo derived particles are virtually identical, structurally and compositionally, to liposome-like lipolytic surface remnants of triglyceride (TG)-rich lipoproteins produced during in vitro lipolysis of hypertriglyceridemic serum. In vitro lipolysis of isolated very-low-density lipoprotein has shown that the lipolytic surface remnants remain attached to the core remnants in the absence of high-density lipoprotein (HDL), dissociate to form liposomelike vesicles in the presence of low levels of HDL, and are assimilated into HDL to form larger HDL particles in the presence of excess HDL. Thus, the in vitro produced, liposome-like particles represent a complex of lipolytic surface C holesterol deposition in the arterial intima is characteristic of human atherosclerotic plaques. 1 These deposits represent both intracellular lipid droplets (foam cells) and extracellular lipid particles. The cholesterol deposits in fibrous plaques are predominantly extracellular. 2Several recent studies have shown that atherosclerotic lesions in both humans and experimental animals contain numerous large, extracellular, liposome-like particles, which differ from extracellular spheroidal very-low-density lipoprotein (VLDL)-and low-density lipoprotein (LDL)-like particles and intracellular lipid droplets in foam cells with respect to size and chemical composition. 310 In animal models these particles accumulate before foam cells appear, emphasizing the primacy of these particles in atherogenesis.

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“…During the metabolism of chylomicron TG by LPL, most of the polar lipids are released as vesicular structures (156)(157)(158) and are transferred to HDL by the action of PLTP (159,160), where PE and PC are metabolized by the action of hepatic lipase and LCAT, which do not metabolize SM (161). LPL may also act on glycerophospholipids in chylomicrons (162).…”

Section: Chylomicron and Vldl Smmentioning

confidence: 99%

Absorption and lipoprotein transport of sphingomyelin

Nilsson

Duan

2006

Journal of Lipid Research

224

201

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Dietary sphingomyelin (SM) is hydrolyzed by intestinal alkaline sphingomyelinase and neutral ceramidase to sphingosine, which is absorbed and converted to palmitic acid and acylated into chylomicron triglycerides (TGs). SM digestion is slow and is affected by luminal factors such as bile salt, cholesterol, and other lipids. In the gut, SM and its metabolites may influence TG hydrolysis, cholesterol absorption, lipoprotein formation, and mucosal growth. SM accounts for z20% of the phospholipids in human plasma lipoproteins, of which two-thirds are in LDL and VLDL. It is secreted in chylomicrons and VLDL and transferred into HDL via the ABCA1 transporter. Plasma SM increases after periods of large lipid loads, during suckling, and in type II hypercholesterolemia, cholesterol-fed animals, and apolipoprotein E-deficient mice. SM is thus an important amphiphilic component when plasma lipoprotein pools expand in response to large lipid loads or metabolic abnormalities. It inhibits lipoprotein lipase and LCAT as well as the interaction of lipoproteins with receptors and counteracts LDL oxidation. The turnover of plasma SM is greater than can be accounted for by the turnover of LDL and HDL particles. Some SM must be degraded via receptor-mediated catabolism of chylomicron and VLDL remnants and by scavenger receptor class B type I receptor-mediated transfer into cells. Sphingomyelin (SM) in mammalian cells is colocalized with cholesterol mainly in the plasma membrane and in lysosomal and Golgi membranes. It interacts strongly with cholesterol, and the regulation of SM and cholesterol metabolism are in part coordinated (1, 2). In plasma lipoproteins, SM is the second most abundant polar lipid after phosphatidylcholine (PC). The size of the plasma lipoprotein SM pool in humans is 1-1.5 g, of which approximately two-thirds are in apolipoprotein B (apoB)-containing triglyceride (TG)-rich lipoproteins and LDL. The SM content in most extraneural tissues is 1-2 g/kg. Factors regulating plasma SM concentration have received little attention. It was early shown that the level of SM is increased in hypercholesterolemia and that SM-rich lipoproteins accumulate in arteriosclerotic lesions (3-5). Plasma SM is thus a risk factor for ischemic heart disease (6), and the apoE-deficient (apoE 2/2 ) mouse, which accumulates SM-rich remnant particles in blood (7), has emerged as an important model for studying the role of SM in atherogenesis. The effects of lipoprotein SM in the arterial wall during atherogenesis may be related both to the modification of lipoproteins and to the generation of sphingolipid messengers (i.e., ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate) initiated by SM hydrolysis (8-10). The role of SM metabolites in cell signaling has been the subject of several recent reviews (11)(12)(13)(14)(15)(16). Sphingolipid signals are triggered by numerous stimuli and mediate effects on cell growth and apoptosis and on the activities of inflammatory cells that may be pathogenic as well as protect...

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Metabolic Fate of Chylomicron Phospholipids and Apoproteins in the Rat

Cited by 210 publications

References 49 publications

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Liposome-like particles isolated from human atherosclerotic plaques are structurally and compositionally similar to surface remnants of triglyceride-rich lipoproteins.

Absorption and lipoprotein transport of sphingomyelin

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