Lymphatic lipid transport: sewer or subway?

The lymphatics began receiving attention in the scientific community as early as 1622, when Gasparo Aselli noted the appearance of milky-white vessels in the mesentery of a well-fed dog. Since this time, the lymphatic system has been historically regarded as the sewer of the vasculature, passively draining fluid and proteins from the interstitial spaces (along with lipid from the gut) into the blood. Recent reports, however, suggest that the lymphatic role in lipid transport is an active and intricate process, and that when lymphatic function is compromised, there are systemic consequences to lipid metabolism and transport. This review highlights these recent findings, and suggests future directions for understanding the interplay between lymphatic and lipid biology in health and disease.

[1]  B. Slatko,et al.  Wolbachia Lipoprotein Stimulates Innate and Adaptive Immunity through Toll-like Receptors 2 and 6 to Induce Disease Manifestations of Filariasis , 2009, The Journal of Biological Chemistry.

[2]  E. Rollins,et al.  Intestinal mucosal lymphatic permeability: an electron microscopic study of endothelial vesicles and cell junctions. , 1970, Journal of ultrastructure research.

[3]  F. Bäckhed,et al.  Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor , 2007, Proceedings of the National Academy of Sciences.

[4]  D. Reichl Extravascular circulation of lipoproteins: their role in reverse transport of cholesterol. , 1994, Atherosclerosis.

[5]  Gerard L. Coté,et al.  Image Correlation Algorithm for Measuring Lymphocyte Velocity and Diameter Changes in Contracting Microlymphatics , 2007, Annals of Biomedical Engineering.

[6]  R. Stewart,et al.  Balance point characterization of interstitial fluid volume regulation. , 2009, American journal of physiology. Regulatory, integrative and comparative physiology.

[7]  P. Mortimer,et al.  Recent advances in breast cancer-related lymphedema of the arm: lymphatic pump failure and predisposing factors. , 2009, Lymphatic research and biology.

[8]  P. Tso,et al.  Role of lymph flow in intestinal chylomicron transport. , 1985, The American journal of physiology.

[9]  Melody A Swartz,et al.  A tissue‐engineered model of the intestinal lacteal for evaluating lipid transport by lymphatics , 2009, Biotechnology and Bioengineering.

[10]  H. Brorson,et al.  Circumferential suction‐assisted lipectomy for lymphoedema after surgery for breast cancer , 2009, The British journal of surgery.

[11]  Shi Ke,et al.  Quantitative imaging of lymph function. , 2007, American journal of physiology. Heart and circulatory physiology.

[12]  Valery V Tuchin,et al.  In vivo multispectral, multiparameter, photoacoustic lymph flow cytometry with natural cell focusing, label‐free detection and multicolor nanoparticle probes , 2008, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[13]  H. Dvorak,et al.  T1α/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema , 2003, The EMBO journal.

[14]  Guillermo Oliver,et al.  Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity , 2005, Nature Genetics.

[15]  C. M. Quick,et al.  Lymphatic pump-conduit duality: contraction of postnodal lymphatic vessels inhibits passive flow. , 2009, American journal of physiology. Heart and circulatory physiology.

[16]  S. Vignes,et al.  Primary intestinal lymphangiectasia (Waldmann's disease) , 2008 .

[17]  M. Guardiola,et al.  Prox-1 and FOXC2 gene expression in adipose tissue: A potential contributory role of the lymphatic system to familial combined hyperlipidaemia. , 2009, Atherosclerosis.

[18]  Christopher J. H. Porter,et al.  Intestinal Lymphatic Transport Enhances the Post-Prandial Oral Bioavailability of a Novel Cannabinoid Receptor Agonist Via Avoidance of First-Pass Metabolism , 2009, Pharmaceutical Research.

[19]  R. Senie,et al.  Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis , 2001, Cancer.

[20]  Michael J. Davis,et al.  Inhibition of the active lymph pump by flow in rat mesenteric lymphatics and thoracic duct , 2002, The Journal of physiology.

[21]  W O Dobbins,et al.  Intestinal mucosal lacteal in transport of macromolecules and chylomicrons. , 1971, The American journal of clinical nutrition.

[22]  M. Suzuki,et al.  Increased lymphocyte transport by lipid absorption in rat mesenteric lymphatics. , 1987, The American journal of physiology.

[23]  P. Carmeliet,et al.  Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. , 2008, The Journal of clinical investigation.

[24]  Gerard L Coté,et al.  Measuring microlymphatic flow using fast video microscopy. , 2005, Journal of biomedical optics.

[25]  D. Zawieja,et al.  Phasic contractions of rat mesenteric lymphatics increase basal and phasic nitric oxide generation in vivo. , 2009, American journal of physiology. Heart and circulatory physiology.

[26]  Dona M. Bondy,et al.  Regulation of lymphatic capillary regeneration by interstitial flow in skin. , 2007, American journal of physiology. Heart and circulatory physiology.

[27]  Jon M. Fukuto,et al.  Shear Stress‐Induced Release of Nitric Oxide From Endothelial Cells Grown on Beads , 1991, Hypertension.

[28]  G. Schmid-Schönbein,et al.  The primary valves in the initial lymphatics during inflammation. , 2007, Lymphatic research and biology.

[29]  K. Greco,et al.  Lymphatic system changes in diabetes mellitus: role of insulin and hyperglycemia , 2005, Diabetes/metabolism research and reviews.

[30]  J. Griffin,et al.  Endothelial and antithrombotic actions of HDL. , 2006, Circulation research.

[31]  M. Swartz,et al.  Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. , 2006, Microvascular research.

[32]  J. Iqbal,et al.  Intestinal lipid absorption. , 2009, American journal of physiology. Endocrinology and metabolism.

[33]  P. Sucharda,et al.  Angiogenic factors are elevated in overweight and obese individuals , 2005, International Journal of Obesity.

[34]  W. MacNaughton,et al.  Contractile activity of lymphatic vessels is altered in the TNBS model of guinea pig ileitis. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[35]  David Zawieja,et al.  Molecular and functional analyses of the contractile apparatus in lymphatic muscle , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  C. Habold,et al.  Morphological changes of the rat intestinal lining in relation to body stores depletion during fasting and after refeeding , 2007, Pflügers Archiv - European Journal of Physiology.

[37]  J. Scholz,et al.  A model of the isolated perfused rat small intestine. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[38]  R. Jain,et al.  Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. , 1997, Science.

[39]  G. Oliver,et al.  Prox1 Function Is Required for the Development of the Murine Lymphatic System , 1999, Cell.

[40]  J. Humphrey Vascular Adaptation and Mechanical Homeostasis at Tissue, Cellular, and Sub-cellular Levels , 2007, Cell Biochemistry and Biophysics.

[41]  G. Schmid-Schönbein,et al.  Evidence for a second valve system in lymphatics: endothelial microvalves , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  E Jenny Heathcote,et al.  Orphanet Journal of Rare BioMed Central Review Primary biliary cirrhosis , 2008 .

[43]  D. Sheppard,et al.  Integrin-α9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis , 2009, Developmental cell.

[44]  N. Piller,et al.  A systematic review of common conservative therapies for arm lymphoedema secondary to breast cancer treatment. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[45]  M. Sayette,et al.  Liprin (beta)1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity. , 2010, Blood.

[46]  J. Hitomi,et al.  Live imaging of lymphatic development in the zebrafish , 2006, Nature Medicine.

[47]  K. Alitalo,et al.  Dermal collagen and lipid deposition correlate with tissue swelling and hydraulic conductivity in murine primary lymphedema. , 2010, The American journal of pathology.

[48]  R. Hovorka,et al.  Mass kinetics of apolipoprotein A-I in interstitial fluid after administration of intravenous apolipoprotein A-I/lecithin discs in humans , 2006, Journal of Lipid Research.

[49]  G. Koh,et al.  Lymphatic development in mouse small intestine , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[50]  S. Woods,et al.  Fasting and postprandial concentrations of GLP-1 in intestinal lymph and portal plasma: evidence for selective release of GLP-1 in the lymph system. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[51]  P. Scherer,et al.  Mechanisms of obesity and related pathologies: The macro‐ and microcirculation of adipose tissue , 2009, The FEBS journal.

[52]  R. Busse,et al.  Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation , 1999, Nature.

[53]  A. McTiernan,et al.  Risk factors for arm lymphedema following breast cancer diagnosis in Black women and White women , 2008, Breast Cancer Research and Treatment.

[54]  R. Shivdasani,et al.  Loss of the PlagL2 transcription factor affects lacteal uptake of chylomicrons. , 2007, Cell metabolism.

[55]  W. Olszewski,et al.  Lipid and apolipoprotein concentrations in prenodal leg lymph of fasted humans. Associations with plasma concentrations in normal subjects, lipoprotein lipase deficiency, and LCAT deficiency. , 2000, Journal of lipid research.

[56]  M. Dewerchin,et al.  Deficiency of vascular endothelial growth factor-D does not affect murine adipose tissue development. , 2009, Biochemical and biophysical research communications.

[57]  D. Zawieja,et al.  Methods for Lymphatic Vessel Culture and Gene Transfection , 2009, Microcirculation.

[58]  David C Zawieja,et al.  Lymphatic smooth muscle: the motor unit of lymph drainage. , 2004, The international journal of biochemistry & cell biology.

[59]  W. Olszewski,et al.  Variations in lipid and apolipoprotein concentrations in human leg lymph: effects of posture and physical exercise. , 2004, Atherosclerosis.

[60]  J. Colombel,et al.  The forgotten role of lymphangitis in Crohn’s disease , 2007, Gut.

[61]  E. Fisher,et al.  Dyslipidemia associated with atherosclerotic disease systemically alters dendritic cell mobilization. , 2004, Immunity.

[62]  Melody A. Swartz,et al.  Transmural Flow Modulates Cell and Fluid Transport Functions of Lymphatic Endothelium , 2010, Circulation research.

[63]  Sanford L. Palay,et al.  An Electron Microscopic Study of the Intestinal Villus: II. The Pathway of Fat Absorption , 1959 .

[64]  A. Gashev,et al.  Rate‐sensitive contractile responses of lymphatic vessels to circumferential stretch , 2009, The Journal of physiology.

[65]  M. Servelle Congenital malformation of the lymphatics of the small intestine. , 1991, Journal of Cardiovascular Surgery.

[66]  Sai T Reddy,et al.  Hypercholesterolemic mice exhibit lymphatic vessel dysfunction and degeneration. , 2009, The American journal of pathology.

[67]  Federica Boschetti,et al.  Synergy between interstitial flow and VEGF directs capillary morphogenesis in vitro through a gradient amplification mechanism. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[68]  Y. Collan,et al.  The lymphatic pump of the intestinal villus of the rat. , 1970, Scandinavian journal of gastroenterology.

[69]  W. Olszewski,et al.  Composition and ultrastructure of size subclasses of normal human peripheral lymph lipoproteins: quantification of cholesterol uptake by HDL in tissue fluids. , 2001, Journal of lipid research.

[70]  G. Azzali The ultrastructural basis of lipid transport in the absorbing lymphatic vessel. , 1982, Journal of submicroscopic cytology.

[71]  J. R. Casley-Smith THE IDENTIFICATION OF CHYLOMICRA AND LIPOPROTEINS IN TISSUE SECTIONS AND THEIR PASSAGE INTO JEJUNAL LACTEALS , 1962, The Journal of cell biology.

[72]  Gerard L Cote,et al.  Lymph Flow, Shear Stress, and Lymphocyte Velocity in Rat Mesenteric Prenodal Lymphatics , 2006, Microcirculation.

[73]  D. Zawieja,et al.  Regional Variations of Contractile Activity in Isolated Rat Lymphatics , 2004, Microcirculation.

[74]  L. Helyer,et al.  Obesity is a Risk Factor for Developing Postoperative Lymphedema in Breast Cancer Patients , 2010, The breast journal.

[75]  K. Alitalo,et al.  Lymphangiogenesis: Molecular Mechanisms and Future Promise , 2010, Cell.

[76]  H. Brorson Liposuction in arm lymphedema treatment. , 2003, Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society.

[77]  Elisabetta Dejana,et al.  Functionally specialized junctions between endothelial cells of lymphatic vessels , 2007, The Journal of experimental medicine.

[78]  R. Lijnen,et al.  Modulation of angiogenesis during adipose tissue development in murine models of obesity. , 2005, Endocrinology.