DOCSLIB.ORG

Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics International Journal of Molecular Sciences Concept Paper Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics Milica Markovic 1 , Shimon Ben-Shabat 1, Aaron Aponick 2 , Ellen M. Zimmermann 3 and Arik Dahan 1,* 1 Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; [email protected] (M.M.); [email protected] (S.B.-S.) 2 Department of Chemistry, University of Florida, Gainesville, FL 32603, USA; [email protected]fl.edu 3 Department of Medicine, Division of Gastroenterology, University of Florida, Gainesville, FL 32610, USA; [email protected]fl.edu * Correspondence: [email protected] Received: 13 April 2020; Accepted: 2 May 2020; Published: 4 May 2020 Abstract: The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented. Lipids can also be conjugated to a drug molecule, accomplishing numerous potential benefits, one being the improved treatment effect, due to joined influence of the lipid carrier and the drug moiety. In addition, such conjugates have increased lipophilicity relative to the parent drug. This leads to improved drug pharmacokinetics and bioavailability, the ability to join endogenous lipid pathways and achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable overcoming different barriers in the body. Altogether, novel mechanisms of the lipid role in diseases are constantly discovered, and new ways to exploit these mechanisms for the optimal drug design that would advance different drug delivery/therapy aspects are continuously emerging. Keywords: lipid; fatty acid; glyceride; steroid; phospholipid; oral drug absorption; prodrug; phospholipase A2 (PLA2) 1. Introduction Lipids are hydrophobic biomolecules, which include fatty acids (FA), glycerides, phospholipids (PL), sterols, sphingolipids, and prenol lipids (Figure1)[ 1]. Lipids play an important role in energy metabolism and storage, as structural components, in signaling, and as hormones. The disruption of lipid metabolic enzymes and pathways occurs in many disease such as cancer, diabetes, infectious, neurodegenerative, and inflammatory diseases [2]. The aim of this work is to elucidate the effect of lipids, and lipid excipients on drug absorption, to describe the metabolic lipid pathways and to demonstrate the role that lipids have in many pathological conditions, as well as their endogenous pharmacological activity. An additional section is dedicated to lipidic prodrugs that can exploit lipid processing pathways in order to achieve their effect. The presence of dietary lipids or lipids from drug formulations/lipidic prodrugs can influence drug absorption by incorporating to the natural lipid metabolic pathways. Hereinafter, we provide a small overview of the lipid influence on drug absorption. Int. J. Mol. Sci. 2020, 21, 3248; doi:10.3390/ijms21093248 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 3248 2 of 15 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 15 Figure 1.1. Main lipid categories: examples of chemical structures. Molecular revolution, such as development of in-vitroin-vitro high-throughputhigh-throughput screening methods and combinatorial chemistry,chemistry, resulted resulted in ain high a high number number of poor of aqueouspoor aqueous solubility solubility molecules molecules to be selected to be asselected drug candidates.as drug candidates. Nearly 40% Nearly of all 40% novel of drugall novel candidates drug candidates are lipophilic are lipophilic and demonstrate and demonstrate low water solubilitylow water [solubility3,4]. Following [3,4]. Following oral administration, oral administration, drugs encounter drugs encounter various obstaclesvarious obstacles on their on way their to theway blood to the circulation. blood circulation. Absorption Absorption is a process, is a process, in which in which orally o administeredrally administered compounds compounds travel travel from thefrom gastrointestinal the gastrointestinal (GI) lumen (GI) into lumen the intestinal into the membrane intestinal and entermembrane systemic and circulation enter systemic/become bioavailable.circulation/become Following bioavailable. ingestion Following and prior ingestion to permeation, and prior the drugto permeation, has to be dissolvedthe drug has in the to GIbe milieudissolved and in turn the GI into milieu a molecular and turn form into closea molecular to the form intestinal closemembrane. to the intestinal This membrane. can be diffi Thiscult can for lipophilicbe difficult compounds for lipophilic with compounds poor solubility with inpoor water, solubility thereby in presenting water, thereby a limiting presenting step in a the limiting absorption step process.in the absorption The presence process. of lipids The derivedpresence from of lipids food orderived lipid-based from formulationsfood or lipid- inbased the intestinalformulations lumen in canthe intestinal influence lumen the oral can absorption influence of the highly oral absorption lipophilic drugs of highly in many lipophilic different drugs ways. in many Thesolubility different ofways. the drugThe solubility can be increased, of the drug due can to be the increased, creation of due various to the colloidalcreation of formations various colloidal (vesicles, formations micelles). Drug(vesicles, solubilization micelles). can Drug be influenced solubilization by lipid can presence be influenced itself and by thelipid simulation presence of physiologicalitself and by lipid the processingsimulation pathways,of physiological leading lipid to processing increased secretion pathways, of leading bile-salts to andincreased phospholipids secretion [of5, 6bile]. The-salts lipids and canphospholipids influence intestinal [5,6]. The metabolism lipids can and influence influx/e fflintestinalux transport. metabolism Studies and showed influx/efflux that, in some transport. cases, lipidStudies excipients showed couldthat, improvein some cases, drug absorptionlipid excipients through could the improve influence drug on the absorption P-glycoprotein through (P-gp) the functioninginfluence on [7 ].the Additionally, P-glycoprotein nuclear (P-gp) hormone functioning receptors [7]. (NHR) Additionally, were shown nuclear to play hormone an important receptors role in(NHR) lipid trawerefficking shown and to metabolism play an important and, thus, role in intestinal in lipid lipid trafficking and drug and absorption, metabolism since and, they thus, control in aintestinal number lipid of proteins and drug (e.g., absorption, fatty-acid-binding since they proteins) control a that number are involved of proteins in lipid (e.g./drug, fatty transport-acid-binding and metabolismproteins) that [8– 10are]. Followinginvolved oralin administration,lipid/drug transport in many and cases metabolism drugs pass through[8–10]. theFollowing hepatic veinoral onadministration, their way to thein many systemic cases blood, drugs whereas pass through highly the lipophilic hepatic compounds vein on their may way be to transported the systemic through blood, thewhereas intestinal highly lymphatic lipophilic system. compounds Lipids canmay also be stimulatetransported intestinal through lymphatic the intestinal drug transport,lymphatic in system. which theLipids drugs can can also bypass stimulate the first-passintestinal hepaticlymphatic metabolism drug transport, and go in directly which tothe the drugs systemic can bypass circulation the first [11].- Afterpass hepatic solubilization, metabolism drugs and permeate go directly through to the the systemic intestinal circulation membrane [11]. via After passive solubilization, diffusion/ activedrugs transportpermeate throughthrough thethe enterocytes.intestinal membrane For hydrophilic via passive drugs diffusion/active with poor solubility transport in lipids, through this stepthe canenterocytes. be the rate-limiting For hydrophilic in the drugs absorption with poor cascade, solubili whereas,ty in lipids, for lipophilic this step drugs,can be thethe unstirredrate‐limiting water in layerthe absorption (UWL) in cascade, the proximity whereas, of the for intestinal lipophilic membrane drugs, the is anunstirred obstacle water for e fflayerective (UWL) permeability. in the Theproximity diffusion of the of FA, intestinal monoglycerides membrane (MG), is an and obstacle many for other effective lipophilic permeability. molecules (includingThe diffusion drugs of andFA, prodrugs)monoglyce throughrides (MG), UWL and is many significantly other lipophilic increased molecules through micellar(including solubilization, drugs and prodrugs) prior to arrivingthrough UWL is significantly increased through micellar solubilization, prior to arriving to the enterocytes. It is likely these lipophilic molecules dissociate from the micelles prior to going into enterocytes or Int. J. Mol. Sci. 2020, 21, 3248 3 of 15 to the enterocytes. It is likely these lipophilic molecules dissociate from the micelles prior to going into enterocytes or through binding to the transporter or vesicular-mediated
Load more

Recommended publications
  • Corticosteroid Treatment, Serum Lipids and Coronary Artery Disease D. B. JEFFERYS M
    Postgrad Med J: first published as 10.1136/pgmj.56.657.491 on 1 July 1980. Downloaded from Postgraduate Medical Journal (July 1980) 56, 491-493 Corticosteroid treatment, serum lipids and coronary artery disease D. B. JEFFERYS M. H. LESSOF B.Sc., M.R.C.P. M.D., F.R.C.P. M. B. MATTOCK Ph.D. Department of Medicine, Guy's Hospital, London Bridge SE] 9RT Summary cholesterol out of the tissue and back into the general Serum lipids and the cholesterol concentrations in the metabolic pool, where it may be catabolized. high density lipoprotein (HDL) fractions were meas- In this study the authors have looked at the long- ured in patients receiving long-term corticosteroid term effects of corticosteroids on HDL cholesterol. treatment for connective tissue disorders and asthma. They have studied 3 groups: patients who are receiv- Patients who were not receiving corticosteroid ing corticosteroids; age-, sex- and disease-matched treatment had blood lipid levels which did not differ patients who are not receiving such treatment; and from those of healthy people. However, female (but healthy age- and sex-matched controls. not male) patients who had received prednisolone for a mean period of 3-1 years had a significant elevation Patients and methods in total cholesterol and a large decrease in HDL Subjects cholesterol. It seems possible that high levels of The serum total cholesterol, triglycerides and copyright. corticosteroids may increase the incidence of pre- HDL cholesterol were measured for 16 pre-meno- menopausal ischaemic heart disease in females. pausal female patients (age range 18-34 years) and 15 males (ages 24-38 years) who were all receiving Introduction long-term corticosteroid treatment.
    [Show full text]
  • De Novo Phosphatidylcholine Synthesis in Intestinal Lipid Metabolism and Disease
    De Novo Phosphatidylcholine Synthesis in Intestinal Lipid Metabolism and Disease by John Paul Kennelly A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Nutrition and Metabolism Department of Agricultural, Food and Nutritional Science University of Alberta © John Paul Kennelly, 2018 Abstract Phosphatidylcholine (PC), the most abundant phospholipid in eukaryotic cells, is an important component of cellular membranes and lipoprotein particles. The enzyme CTP: phosphocholine cytidylyltransferase (CT) regulates de novo PC synthesis in response to changes in membrane lipid composition in all nucleated mammalian cells. The aim of this thesis was to determine the role that CTα plays in metabolic function and immune function in the murine intestinal epithelium. Mice with intestinal epithelial cell-specific deletion of CTα (CTαIKO mice) were generated. When fed a chow diet, CTαIKO mice showed normal lipid absorption after an oil gavage despite a ~30% decrease in small intestinal PC concentrations relative to control mice. These data suggest that biliary PC can fully support chylomicron output under these conditions. However, when acutely fed a high-fat diet, CTαIKO mice showed impaired intestinal fatty acid and cholesterol uptake from the intestinal lumen into enterocytes, resulting in lower postprandial plasma triglyceride concentrations. Impaired intestinal fatty acid uptake in CTαIKO mice was linked to disruption of intestinal membrane lipid transporters (Cd36, Slc27a4 and Npc1l1) and higher postprandial plasma Glucagon-like Peptide 1 and Peptide YY. Unexpectedly, there was a shift in expression of bile acid transporters to the proximal small intestine of CTαIKO mice, which was associated with enhanced biliary bile acid, PC and cholesterol output relative to control mice.
    [Show full text]
  • Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses
    life Review Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses Inseok Choi , Hyewon Son and Jea-Hyun Baek * School of Life Science, Handong Global University, Pohang, Gyeongbuk 37554, Korea; [email protected] (I.C.); [email protected] (H.S.) * Correspondence: [email protected]; Tel.: +82-54-260-1347 Abstract: The tricarboxylic acid cycle (TCA) is a series of chemical reactions used in aerobic organisms to generate energy via the oxidation of acetylcoenzyme A (CoA) derived from carbohydrates, fatty acids and proteins. In the eukaryotic system, the TCA cycle occurs completely in mitochondria, while the intermediates of the TCA cycle are retained inside mitochondria due to their polarity and hydrophilicity. Under cell stress conditions, mitochondria can become disrupted and release their contents, which act as danger signals in the cytosol. Of note, the TCA cycle intermediates may also leak from dysfunctioning mitochondria and regulate cellular processes. Increasing evidence shows that the metabolites of the TCA cycle are substantially involved in the regulation of immune responses. In this review, we aimed to provide a comprehensive systematic overview of the molecular mechanisms of each TCA cycle intermediate that may play key roles in regulating cellular immunity in cell stress and discuss its implication for immune activation and suppression. Keywords: Krebs cycle; tricarboxylic acid cycle; cellular immunity; immunometabolism 1. Introduction The tricarboxylic acid cycle (TCA, also known as the Krebs cycle or the citric acid Citation: Choi, I.; Son, H.; Baek, J.-H. Tricarboxylic Acid (TCA) Cycle cycle) is a series of chemical reactions used in aerobic organisms (pro- and eukaryotes) to Intermediates: Regulators of Immune generate energy via the oxidation of acetyl-coenzyme A (CoA) derived from carbohydrates, Responses.
    [Show full text]
  • Fatty Acid Synthesis ANSC/NUTR 618 Lipids & Lipid Metabolism Fatty Acid Synthesis I
    Handout 5 Fatty Acid Synthesis ANSC/NUTR 618 Lipids & Lipid Metabolism Fatty Acid Synthesis I. Overall concepts A. Definitions 1. De novo synthesis = synthesis from non-fatty acid precursors a. Carbohydrate precursors (glucose and lactate) 1) De novo fatty acid synthesis uses glucose absorbed from the diet rather than glucose synthesized by the liver. 2) De novo fatty acid synthesis uses lactate derived primarily from glucose metabolism in muscle and red blood cells. b. Amino acid precursors (e.g., alanine, branched-chain amino acids) 1) De novo fatty acid synthesis from amino acids is especially important during times of excess protein intake. 2) Use of amino acids for fatty acid synthesis may result in nitrogen overload (e.g., the Atkins diet). c. Short-chain organic acids (e.g., acetate, butyrate, and propionate) 1) The rumen of ruminants is a major site of short-chain fatty acid synthesis. 2) Only small amounts of acetate circulate in non-ruminants. 2. Lipogenesis = fatty acid or triacylglycerol synthesis a. From preformed fatty acids (from diet or de novo fatty acid synthesis) b. Requires source of carbon (from glucose or lactate) for glycerol backbone 3T3-L1 Preadipocytes at confluence. No lipid 3T3-L1 Adipocytes after 6 days of filling has yet occurred. differentiation. Dark spots are lipid droplets. 1 Handout 5 Fatty Acid Synthesis B. Tissue sites of de novo fatty acid biosynthesis 1. Liver. In birds, fish, humans, and rodents (approx. 50% of fatty acid biosynthesis). 2. Adipose tissue. All livestock species synthesize fatty acids in adipose tissue; rodents synthesize about 50% of their fatty acids in adipose tissue.
    [Show full text]
  • Aandp2ch25lecture.Pdf
    Chapter 25 Lecture Outline See separate PowerPoint slides for all figures and tables pre- inserted into PowerPoint without notes. Copyright © McGraw-Hill Education. Permission required for reproduction or display. 1 Introduction • Most nutrients we eat cannot be used in existing form – Must be broken down into smaller components before body can make use of them • Digestive system—acts as a disassembly line – To break down nutrients into forms that can be used by the body – To absorb them so they can be distributed to the tissues • Gastroenterology—the study of the digestive tract and the diagnosis and treatment of its disorders 25-2 General Anatomy and Digestive Processes • Expected Learning Outcomes – List the functions and major physiological processes of the digestive system. – Distinguish between mechanical and chemical digestion. – Describe the basic chemical process underlying all chemical digestion, and name the major substrates and products of this process. 25-3 General Anatomy and Digestive Processes (Continued) – List the regions of the digestive tract and the accessory organs of the digestive system. – Identify the layers of the digestive tract and describe its relationship to the peritoneum. – Describe the general neural and chemical controls over digestive function. 25-4 Digestive Function • Digestive system—organ system that processes food, extracts nutrients, and eliminates residue • Five stages of digestion – Ingestion: selective intake of food – Digestion: mechanical and chemical breakdown of food into a form usable by
    [Show full text]
  • Regulation of ATP-Binding Cassette Transporter Al in Cholesteryl Ester Storage Disease
    Regulation of ATP-Binding Cassette Transporter Al In Cholesteryl Ester Storage Disease by NICOLAS JAMES BILBEY B.Sc (Honours), Thompson Rivers University, 2006 A THESIS SUBMiTTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2009 © Nicolas James Bilbey, 2009 ABSTRACT Previous studies from the Francis laboratory have determined that regulation of ABCA1 expression is impaired in the lysosomal cholesterol storage disorder Niemann-Pick type C (NPC) disease, the presumed reason for the low plasma HDL-cholesterol (HDL-C) levels found in the majority of NPC disease patients. Cholesteryl ester storage disease (CESD) is another lysosomal cholesterol storage disorder, resulting from deficiency in lysosomal acid lipase (LAL). CESD patients develop premature atherosclerosis, possibly related to their known low plasma HDL-C levels. We hypothesized that in CESD the reduced activity of LAL also leads to impaired ABCA1 regulation and HDL formation due to the decrease in release of unesterified cholesterol from lysosomes. Our results show that human CESD fibroblasts exhibit a blunted increase in ABCA1 mRNA and protein in response to addition of low density lipoprotein (LDL) to the medium when compared to normal human fibroblasts. Efflux of LDL-derived cholesterol radiolabel and mass to apolipoprotein A-I-containing medium was markedly reduced in CESD fibroblasts compared to normal fibroblasts. Cellular radiolabeled cholesteryl ester derived from LDL and total cell cholesteryl ester mass was increased in CESD compared to normal cells. Delivery of an adenovirus expressing full length human lysosomal acid lipase (Ad-hLAL) results in correction of LAL activity and an increase ABCA1 protein expression, as well as correction of cholesterol and phospholipid release to apoA-I and normalization of cholesteryl ester levels in the CESD fibroblasts.
    [Show full text]
  • Lipid Metabolism
    Objectives By the end of lecture the student should: Discuss β oxidation of fatty acids. Illustrate α oxidation of fatty acids. Understand ω oxidation of fatty acids. List sources and fates of active acetate. Oxidation of Fatty Acids 1- β-Oxidation (knoop’s oxidation): . Removal of 2 carbon fragment at a time form Acyl CoA (active FA). .The 2 carbon removed as acetyl CoA. .It occurs in many tissues including liver, kidney & heart FAs to be oxidized must be entered the following 2 steps 2- Transport of acyl 1-Activation of FA COA to mitochondria 1-FA activation Acyl COA synthetase RCOOH RCO~SCOA COASH ATP AMP+P~P 2Pi + E Pyrophosphatase 2- Transport of acyl COA to mitochondria: . Role of carnitine in the transport of LCFA through the inner mithochochondrial membrane Functions of carnitine 1- Transport long chain acyl COA across mitochondrial membrane into the mitochondria so it increases the rate of oxidation of LCFA 2- Transport acetyl-CoA from mitochondria to cytoplasm So it stimulates fatty acid synthesis CoA CoA--SHSH H C α H3C3 α β Cβ Palmitoyl Palmitoyl-CoA -CoA β O ~ S – CoA α H3C α H3C β β CO CO ~ S~ –S CoA – CoA β + + CH3 – CO ~ S –CoA Successive removal of C2 units Acetyl-CoA 8CH3 – CO ~ S – CoA 8CH3 – CO ~ S –Acetyl CoA-CoA Acetyl-CoA Steps of β- Oxidation of FAs Energetics of FA oxidation Palmitic (16C): . β-oxidation of palmitic acid will be repeated 7 cycles producing 8 molecules of acetyl COA . In each cycle FADH2 and NADH+H+ is produced & transported to respiratory chain FADH2 ------------------ 2 ATP NADH+H+ ------------- 3 ATP So 7 cycles 5X7=35 ATP .
    [Show full text]
  • Regulation of Ketone Body and Coenzyme a Metabolism in Liver
    REGULATION OF KETONE BODY AND COENZYME A METABOLISM IN LIVER by SHUANG DENG Submitted in partial fulfillment of the requirements For the Degree of Doctor of Philosophy Dissertation Adviser: Henri Brunengraber, M.D., Ph.D. Department of Nutrition CASE WESTERN RESERVE UNIVERSITY August, 2011 SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of __________________ Shuang Deng ____________ _ _ candidate for the ________________________________degree Doctor of Philosophy *. (signed) ________________________________________________ Edith Lerner, PhD (chair of the committee) ________________________________________________ Henri Brunengraber, MD, PhD ________________________________________________ Colleen Croniger, PhD ________________________________________________ Paul Ernsberger, PhD ________________________________________________ Janos Kerner, PhD ________________________________________________ Michelle Puchowicz, PhD (date) _______________________June 23, 2011 *We also certify that written approval has been obtained for any proprietary material contained therein. I dedicate this work to my parents, my son and my husband TABLE OF CONTENTS Table of Contents…………………………………………………………………. iv List of Tables………………………………………………………………………. viii List of Figures……………………………………………………………………… ix Acknowledgements………………………………………………………………. xii List of Abbreviations………………………………………………………………. xiv Abstract…………………………………………………………………………….. xvii CHAPTER 1: KETONE BODY METABOLISM 1.1 Overview……………………………………………………………………….. 1 1.1.1 General introduction
    [Show full text]
  • CHAPTER-IV LIPID METABOLISM BETA-OXIDATION Beta-Oxidation Is
    CHAPTER-IV LIPID METABOLISM BETA-OXIDATION Beta-oxidation is the process by which fatty acids, in the form of acyl-CoA molecules, are broken down in mitochondria and/or peroxisomes to generate acetyl-CoA, the entry molecule for the citric acid cycle. The beta oxidation of fatty acids involve three stages: 1. Activation of fatty acids in the cytosol 2. Transport of activated fatty acids into mitochondria (carnitine shuttle) 3. Beta oxidation proper in the mitochondrial matrix Fatty acids are oxidized by most of the tissues in the body. However, some tissues such as the adrenal medulla do not use fatty acids for their energy requirements and instead use carbohydrates. Energy yield The ATP yield for every oxidation cycle is 14 ATP (according to the P/O ratio), broken down as follows: Source ATP Total [citation needed] 1 FADH2 x 1.5 ATP = 1.5 ATP (some sources say 2 ATP) 1 NADH x 2.5 ATP = 2.5 ATP (some sources say 3 ATP) 1 acetyl CoA x 10 ATP = 10 ATP (some sources say 12 ATP) TOTAL = 14 ATP For an even-numbered saturated fat (C2n), n - 1 oxidations are necessary, and the final process yields an additional acetyl CoA. In addition, two equivalents of ATP are lost during the activation of the fatty acid. Therefore, the total ATP yield can be stated as: (n - 1) * 14 + 10 - 2 = total ATP For instance, the ATP yield of palmitate (C16, n = 8) is: (8 - 1) * 14 + 10 - 2 = 106 ATP Represented in table form: Source ATP Total 7 FADH2 x 1.5 ATP = 10.5 ATP 7 NADH x 2.5 ATP = 17.5 ATP 8 acetyl CoA x 10 ATP = 80 ATP Activation = -2 ATP NET = 106 ATP For sources that use the larger ATP production numbers described above, the total would be 129 ATP ={(8-1)*17+12-2} equivalents per palmitate.
    [Show full text]
  • University of Cincinnati
    UNIVERSITY OF CINCINNATI Date:___________________ I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of: in: It is entitled: This work and its defense approved by: Chair: _______________________________ _______________________________ _______________________________ _______________________________ _______________________________ ii Intestinal lipid uptake and secretion of VLDL and chylomicron By: Andromeda Nauli August 2005 Previous degree: Bachelor of Science in Biomedical Sciences Degree to be conferred: Ph.D. Department of Pathology and Laboratory Medicine College of Medicine University of Cincinnati Committee chair: Patrick Tso, Ph.D. iii ABSTRACT Despite decades of research, our understanding of intestinal lipid absorption is limited. In this Ph.D. thesis, I have dealt with two main aspects of intestinal lipid absorption, namely the uptake of lipids and the formation and secretion of triacylglycerol-rich lipoproteins (very low density lipoproteins [VLDL] and chylomicrons). In terms of uptake, CD36 is one of the plasma membrane proteins implicated in mediating lipid uptake by the intestine. In order to test this hypothesis, we utilized the CD36 knockout mouse model equipped with intraduodenal and lymph cannulas. Our studies showed that the disruption of the CD36 gene led to a significant decrease in the uptake of cholesterol but not of fatty acids. Interestingly, the role of CD36 was not limited to uptake but also appeared to affect the formation and secretion of chylomicrons, the major lipoproteins carrying the absorbed dietary fat from the gut (Chapter 2). It was first proposed by Tso et al. (202) that the small intestine secretes both VLDL and chylomicrons. Previous work by Vahouny et al. (212) suggested that female rats produced more VLDL than male rats.
    [Show full text]
  • Fat Digestion: Intestinal Lipolysis and Product Absorption
    Nutrition of the Lov: Birthweight Infant, edited by B. L. Salle and P. R. Swyer. Nestte Nutrition Workshop Series, Vol. 32. Nestec Ltd., Vevey/Raven Press, Ltd., New York © 1993. Fat Digestion: Intestinal Lipolysis and Product Absorption Lars Blackberg and *Olle Hernell Department of Medical Biochemistry and Biophysics, and 'Department of Pediatrics, University of Umea, S-901 85 Umea, Sweden Fat digestion in the breastfed newborn infant is a process catalyzed by three Upases. The process is initiated in stomach contents by gastric lipase and continues in the upper part of the small intestine by pancreatic colipase-dependent lipase and human milk bile-salt-stimulated lipase (BSSL). Development of powerful techniques in molecular biology has made it possible to gain better insight into the structure of these lipases, which is necessary for a detailed understanding of the different functional aspects. We shall briefly discuss recent advances in structural knowledge of the lipases as well as their functional implica- tions. We shall focus mainly on the human enzymes but, when relevant, also discuss corresponding enzymes of other species. GASTRIC LIPASE Gastric lipolysis and lipase activities of preduodenal origin have been recognized for many years. In humans the responsible enzyme is secreted by the chief cells of the gastric mucosa (1). The primary sequence of this 52-kDa glycoprotein is known through cloning and sequencing of cDNA (2). The tissue of origin differs between species but the amino acid sequence is highly conserved (2-5). Although, gastric lipase is of similar molecular size to colipase-dependent lipase the sequence shows only limited homology.
    [Show full text]
  • Lipid and Carbohydrate Metabolism in Caenorhabditis Elegans
    | WORMBOOK METABOLISM, PHYSIOLOGY, AND AGING Lipid and Carbohydrate Metabolism in Caenorhabditis elegans Jennifer L. Watts*,1 and Michael Ristow† *School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, Washington 99164 and †Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology Zurich, 8603 Schwerzenbach-Zurich, Switzerland ORCID ID: 0000-0003-4349-0639 (J.L.W.) ABSTRACT Lipid and carbohydrate metabolism are highly conserved processes that affect nearly all aspects of organismal biology. Caenorhabditis elegans eat bacteria, which consist of lipids, carbohydrates, and proteins that are broken down during digestion into fatty acids, simple sugars, and amino acid precursors. With these nutrients, C. elegans synthesizes a wide range of metabolites that are required for development and behavior. In this review, we outline lipid and carbohydrate structures as well as biosynthesis and breakdown pathways that have been characterized in C. elegans. We bring attention to functional studies using mutant strains that reveal physiological roles for specific lipids and carbohydrates during development, aging, and adaptation to changing environmental conditions. KEYWORDS Caenorhabditis elegans; ascarosides; glucose; fatty acids; phospholipids; sphingolipids; triacylglycerols; cholesterol; maradolipids; WormBook TABLE OF CONTENTS Abstract 413 Fatty Acids 415 Characteristics of C. elegans fatty acids 415 Methods
    [Show full text]