Lipid digestion and inter-organ transport Russian National Research Medical University Maxim A. Abakumov Moscow, 2014

Lipids Large group of organic compounds containing long hydrocarbon chains or rings Poorly sooluble in water Well soluble in organic solvents Usually large size molecules

Lipid functions Structural component of biological membranes Energy storage Hormones and vitamins Lipophilic bile acids important for lipid solubilization

Lipid classification Lipids Glycerides Fatty acids SaturatedUnsaturated Neutral glycerides Phospho glycerides Nonglyceride lipidsComplex lipids WaxesSphingolipidsSteroids Lipoproteins

Lipid classification Lipids Glycerides Fatty acids SaturatedUnsaturated Neutral glycerides Phospho glycerides Nonglyceride lipidsComplex lipids WaxesSphingolipidsSteroids Lipoproteins

Fatty acids Carboxylic acids with long (C 8 -C 20 ) hydrocarbon «tail» Saturated fatty acids contain only σ-bonds (single bonds) Unsaturated fatty acids contain also π-bonds (double bonds)

Fatty acids

Saturated fatty acids Have even number of carbon atoms Contain maximum hydrogen atoms Hydrocarbon chains (HC) are full length straight Have high melting point

Unsaturated fatty acids Have even number of carbon atoms Contain less hydrogen atoms then saturated FAs Each doble bond bent HC for 30° Have low melting point

Fatty acids

Trans- and cis-fatty acids Oleic acidElaidic acid Cis double bond Trans double bond

Fatty acids nomenclature

Fatty acids

Essential fatty acids

Lipid classification Lipids Glycerides Fatty acids SaturatedUnsaturated Neutral glycerides Phospho glycerides Nonglyceride lipidsComplex lipids WaxesSphingolipidsSteroids Lipoproteins

Triglycerides

Phospholipids X X Fatty acid chain GlycerolPhosphate

Lipid classification Lipids Glycerides Fatty acids SaturatedUnsaturated Neutral glycerides Phospho glycerides Nonglyceride lipidsComplex lipids WaxesSphingolipidsSteroids Lipoproteins

Sphingolipids Sphingosine RSphingolipid HCeramide PhosphocholineSphyngomyelin SugarGlycosphingolipid

Glycolipids

Fat digestion Most fat is presented as TGs Low water solubility Large size Low accebility for enzymes Bile acids create fat emulsion Size of fat drops decreases Surface increases Accebility for enzymes increases TGs are hydrolized Lipase Colipase Micells are formed Fatty acids are transported into cells

Fat digestion Most fat is presented as TGs Low water solubility Large size Low accebility for enzymes Bile acids create fat emulsion Size of fat drops decreases Surface increases Accebility for enzymes increases

Fat emulsification TGs are hydrophobic- solubilization is needed. Key players – bile acids Bile acids are cholesterol derivatives Synthesized in liver from AcCoA Amphiphilic molecules

Fat emulsification Nonpolar region Polar (charged) region Bile salt Emulsification Fat droplets coated with bile salts are suspended in water

Bile acids

Primary bile acids Synthesized in liver from cholesterol

Secondary bile acids Bacteria in gut

Conjugated bile salts Occurs in liver Both with primary and secondary bile acids Glycine or taurin are conjugated To carboxylic group on bile acid tale Glycine Taurine

Conjugated bile salts Glycoholic acid Tauroholic acid Cholic acid

Enterohepatic circulation of bile acids

Pancreatic lipase Hydrolyse TGs into 2 fatty acids and monoacylglyceride Extracellular enzyme Secreted by pancreas Esterase enzyme subclass

Fat digestion TGs are hydrolized Lipase Colipase Micells are formed Fatty acids are transported into cells

Pancreatic lipase Free fatty acids Pancreatic lipase hydrolase bonds between glycerol and fatty acids at positions 1 and 3 Position 1 Position 3

Colipase Small protein Cofactor for lipase Prevent lipase inactivation by bile salts Required for effecient lipase work in intestine Secreted as procolipase (inactive) Activated by trypsin

Colipase

Long chain TGs Long chain TGs (LCTG)– contain fatty acids with carbon atoms Poor solubility in water Requires bile acids for digestion and transport Resinthesized in intestinal cells Combined with lipoproteins to form chylomicrons Transported in chylomicrons into lymphatic system Can be stored in adipose tissue prior to oxidation in liver

Long chain TGs

Medium chain TGs Medium chain TG (MCTG) – contain fatty acids with 8-10 carbon atoms Higher polarity, then LCTG Bile acids are not required for absorbtion Transported into blood in natural state Faster oxidized in liver Don’t go to adipose tissue

Medium chain TGs

Interorgan lipid transport Lipids are poorly soluble in water Special lipoprotein complexes are used for lipis solubilization Each lipoprotein complex transport lipids in one direction Main directions are 1) Intestine→Liver 2) Liver→Peripheral organs 3) Peripheral organs

Interorgan lipid transport Peripheral tissue Chylomicrons VLDL, LDL, IDLHDL

Lipoproteins in lipid transport

Lipoproteins

Lipoproteins in lipid transport

Chylomicrons Largest lipoprotein Contains largest amount of lipids Transport TGs from intestine to peripheral tissue Transport TGs and cholesterol to liver (remnant chilomicrons) Mostly dietary TGs Main proteins are: B-48, A, C, E Supresses cholesterol biosynthesysis

Chilomicrons

Very low density liporpotein VLDL Mostly contain endogenous TGs and cholesterol. Synthesized in liver Transport endogenous TGs from liver to peripheral tissue Main proteins are: B-100, C, E Same metabolism as chilomicrons except fact that VLDL are synthesized in liver

VLDL

Intermediate density lipoprotein IDL Contain both endogenous TGs and cholesterol esters (CE) Transport TGs and CE to peripheral tissue Synthesized from VLDL in blood stream by lipoprotein lipase (LPL) Main proteins are: B-100, E

Low density lipoprotein LDL Contain more CE then TG Transport CE from liver to peripheral tissue Synthesized from IDL (VLDL) in blood stream Main proteins are: B-100

IDL and LDL VLDL LPL Remnant VLDL (IDL) Liver internalization ApoB-100 (LDL-receptor) LPL HL LDL Liver internalization ApoB-100 (LDL-receptor) Peripheral tissue ApoB-100 (LDL-receptor) FA+cholesterol FA to peripheral tissue FA to peripheral tissue

Type Deficiency Lipid elevated in blood Lipoprotein elevated in blood Comments I Familial lipoprotein lipase(rare) apoC-II (rare) Triglyceride Chylomicro ns Red-orange eruptive xanthomas, Fatty liver Acute pancreatis Abdominal pain after fatty meal IIa Familial hypercholeste rolemia CholesterolLDL High risk of atherosclerosis and coronary artery disease Xanthomas of the Achilles tendon Xanthelasmas Corneal areus

High density lipoproteins HDL Contains largest amount of CE, less TG Transport cholesterol (CE) to liver from peripheral tissues Synthesized in liver and intestine as Apolipoprotein A1 Main protein are: A1

High density lipoproteins