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Download Cell Bio 9- Small Intestinal Phase II Lipids Substances that are
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Cell Bio 9- Small Intestinal Phase II • • • Lipids Substances that are more soluble in organic solvents than water Contain more calories per gram than carbohydrates or protein • Significant nutrition contribution • Excessive consumption → increase risk for obesity and cardiovascular disease Fats and lipids are not interchangeable • Fats or fatty acids are a component of triglycerides, phospholipids and cholesterol esters Triglycerides • Most common lipid found in the human diet (>90%) • Major form of energy storage in adipose tissue • Structure • 3 fatty acid chains • Long-chain (> 12 carbons, most common) • Medium-chain (6-12 carbons) • Short-chain (<6 carbons) • Glycerol backbone Phospholipids • Integral part of cell membrane • Similar structure to triglycerides • Glycerol backbone • 3 ester linked groups • 1st and 2nd position fatty acids • Different • 3rd position phosphate group coupled to a nitrogenous base such as choline or ethanolamine • >75% of the phospholipids in the intestine comes from bile and desquamated enterocytes Cholesterol • Third source of lipids • Integral part of cell membranes • Most commonly consumed from animal fat but can occur in plants • Most of the cholesterol in the intestines come from bile • Smaller amount of cholesterol comes from dietary intake Fatty Acids • Unsaturated-GOOD • Monounsaturated • Single double bond between carbons • Olive, canola, sesame oil, almonds, pistachios, peanuts • Polyunsaturated • Multiple double bonds between carbons • Corn, cottonseed, safflower oil, sunflower seeds, flaxseed, soybeans, tub margarine and seafood • Omega 3 • First double bond occurs at the 3rd carbon (from the end) • DHA (docosahexanoic acid, C 22:6) • EPA (eicosapentanoic acid, C 20:5) • Salmon, sardines and tuna • Trans-BAD • Two hydrogen atoms are bound to opposite sides of the double bond—straight line • CAD plus linked to cancers • Most of what we consume is due to commercial hydrogenation of oils • Does not occur naturally Cell Bio 9- Small Intestinal Phase II • Saturated-BAD • No double bonds • Worse than dietary cholesterol at raising plasma cholesterol levels • 3 essential fatty acids • Fatty acids that must be consumed in the diet because they cannot be synthesized from other foods i. Linolenic acid (9,12,15-octadecatrienoic acid, C 18:3) 1. Omega 3 ii. Linoleic acid iii. Arachidonic acid • DHA and EPA may also be required during development Lipid Digestion • Stomach (mixing) • Emulsification • Suspension of small lipid droplets • Increases surface area • Otherwise the lipids would form a layer floating on top of the aqueous gastric juices • Gastric lipase (10-30%) • Optimal activity at ↓pH • Incomplete digestion of triglycerides • Prefers medium chain fatty acids (common in milk) • Little or no breakdown of cholesterol esters and fat-soluble vitamins • Gastric lipase is not required • Most lipid digestion occurs in the small intestine by 3 pancreatic enzymes (70-95%) 1. Pancreatic lipase • Optimal activity at pH 7-8 • Hydrolyze both the 1 and 3 positions of triglycerides • Free fatty acids • 2-monoacylglycerol • Colipase • Cofactor • Secreted as pro-colipase • Activated by trypsin • Bridging molecule that binds to lipase (1:1) and bile acids • Optimizes lipase activity in the presence of bile acids • Otherwise bile acids would inhibit lipase activity 2. Phospholipase A2 • Secreted by the pancreas • Hydrolyzes phospholipids to lysophospholipids • 2nd ester bond • Phosphatidylcholine (lecithin) is the most common phospholipid • Secreted as a zymogen (pro-phospholipase A2) • Activated by trypsin • Phospholipids are an integral cell membrane protein • Requires bile salts and Ca2+ for activity 3. Cholesterol esterase (carboxyl esterase, cholesterol ester hydrolase) • Hydrolyzes esters of • Cholesterol, Fat-soluble vitamins, Triglycerides • Requires bile acids for activity • Cholesterol esters are less polar than cholesterol and cannot be absorbed • Serve as a storage and transport form of cholesterol Cell Bio 9- Small Intestinal Phase II Micelle Formation • Composed of bile salts and the products of lipid digestion • Critical micellar concentration (certain conc of bile salts in liver for micelles to form) • Amphiphilic bile salts shield the hydrophobic lipids from the aqueous gastric environment • Soluble in aqueous solution • Solubilizes the lipids • Short-chain fatty acids do not require bile salts or micelles for absorption • Increases exposure of the hydrophobic lipids to the epithelial surface for absorption • Bile salt deficiency • Unable to make micelles • Unable to absorb cholesterol and fat-soluble vitamins • Free fatty acids and monoglycerides are soluble enough to be absorbed without causing malabsorption in the absence of bile salts Lipid Absorption • Luminal Transport • Lipids, by their inherent nature, should be capable of crossing cell membranes by passive diffusion (without facilitated transport) • Monoglycerides, FFA, cholesterol and lysolecithin taken up separately • However, additionally and/or alternatively they may cross via selective transport mechanisms • Microvillus membrane fatty acid-binding protein (MVM-FABP) • Long-chain fatty acids • Niemann Pick C1 like 1 (NPC1L1) protein • Cholesterol • Note: Ezetimibe, used in combination therapy to treat hypercholesterolemia, blocks NPC1L1 and the absorption of cholesterol. • Intracellular reconstruction • Reesterification to • Triglycerides • Phospholipids • Cholesterol esters • Occurs in the SER • FFA are activated to form acyl-coenzyme A • Esterify monoglyceride →diglyceride→triglyceride • Cholesterol esterification by acyl-CoA cholesterol acyltransferase • Simultaneous synthesis of apolipoproteins in the RER • Apo B • Combine with reconstructed lipids to form chylomicrons (vehicle where lipids from intestines out) Chylomicrons • Basolateral transport • Lipids are exported as chylomicrons • Chylomicrons are a lipoprotein • Exocytosed into the lymphatics • Too large to cross into the capillaries • Bypass the portal vein and first pass liver metabolism • Enter the blood stream in the thoracic duct • Transported as chylomicrons to target organs • Small-chain and medium-chain fatty acids • Taken up between enterocyte tight junctions into the portal blood • Bypass intracellular reconstruction Cell Bio 9- Small Intestinal Phase II Lipid Assimilation Disorders • Abetalipoproteinemia • Rare • Caused by a mutation of the microsomal triglyceride transfer protein • Resulting in a deficiency in apo B-48 and B-100 • Inability to produce lipoproteins • Do not produce any chylomicrons, VLDLs and LDLs (LDLs are formed from VLDLs) • Unable to transport absorbed fat out of the small intestines • Accumulation of lipids in enterocytes • Have vitamin A,D,E and K deficiency • • • Vitamins Organic compounds required as a nutrient Vitamins cannot be synthesized by the body and must be obtained from the diet Currently 13 compounds are classified as vitamins • FYI: minerals are inorganic Know fat soluble vs water soluble Fat-soluble Vitamins Take in too many fat soluble get stored and can cause problems and • A, D, E, and K toxicity • Vitamin A (Retinol) Too many water soluble, get removed via kidney • Active forms • Retinal and retinoic acid • Sources • Direct from animals or can be converted from β-carotene (carrots) • Absorption • Micellar solubilization and passive absorption • Re-esterified and incorporated into chylomicrons • Taken up and stored in the liver until needed • Note: Vitamin A deficiency can lead to night blindness and skin lesions Cell Bio 9- Small Intestinal Phase II • Vitamin E • Dietary vitamin E is α-tocopherol • High in vegetable oils • Absorbed by passive diffusion and incorporated into chylomicrons • Potent antioxidant • Deficiency • Anemia associated with oxidative damage to red blood cells • Vitamin K • Dietary vitamin K is phylloquinones (phytonadione) • Source green leafy plants • Absorbed via an energy dependent mechanism in the proximal small intestine and incorporated into chylomicrons • Menaquinones (bacterial derived vitamin K) is absorbed passively • Required for the synthesis of clotting factors • Calciferols (Vitamin D)—steroid hormone? • Ergocalciferol is ultraviolet light activated ergosterol • Ergosterol is a fungi synthesized sterol • Ergocalciferol is used as a human supplement called vitamin D2 • Cholecalciferol is ultraviolet light activated 7-dehydrocholesterol • 7-dehydrocholesterol is a sterol synthesized in human skin • Cholecalciferol is used as a human supplement called vitamin D3 (we make this, why is it vitamin • Cholecalciferol occurs naturally in cod liver oil but it is not naturally found in most foods UV Liver 7-dehydrocholesterol → cholecalciferol → 25-hydroxycholecalciferol Kidney → 1,25-dihydroxycholecalciferol (calcitriol) • Calciferol deficiency leads to rickets Water-soluble vitamins • Bs & C • B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid), B6 (pyridoxine), B7 (biotin, vitamin H), B9 (folic acid), B12 (cobalamins) and C (ascorbic acid) • Ascorbic acid • Source: Green vegetables and fruit • Absorption: Na+- dependent active transport system in the ileum • Role : Redox reactions • Deficiency: Scurvy • Thiamine • Source: Grain, yeast and pork • Absorption • Low concentrations: Na+- dependent active transport system in the jejunum • High concentrations: passive diffusion • Role : Carbohydrate metabolism • Deficiency: Beriberi • Riboflavin • Source: Milk, leafy vegetables, liver, yeast, mushrooms and almonds • Absorption • Low concentrations: Na+- dependent active transport system in the jejunum • High concentrations: passive diffusion • Role: Flavoprotein required for metabolism • Deficiency: Anorexia, impaired growth and inflammation of the mouth Cell Bio 9- Small Intestinal Phase II • Niacin • Source • Liver, chicken, beef, fish, cereal and peanuts • Synthesized from tryptophan • Absorption • Low concentrations: Na+- dependent active transport system in the jejunum • High concentrations: passive diffusion • Role: Component of NAD(H) and NADP(H) required for redox reactions • Deficiency: Severe-pellagra • Pantothenic acid (B5) • Source: Everything • In the form of CoA • Absorption • CoA must be converted into free pantothenic acid by a multi-step process. • Free pantothenic acid • Low concentrations: Na+- dependent active transport system in the jejunum • High concentrations: passive diffusion • Role: CoA synthesis • Deficiency: Not applicable • Pyridoxine • Source: Meat, fish, poultry, nuts and fruit • Absorption: Passive diffusion throughout the small intestine • Role: Amino acid and carbohydrate metabolism • Deficiency: Anemia and nervous system disorders • Biotin • Source: Variety of sources none of them are very rich in biotin. Usually protein bound • Absorption • Low concentrations: Na+-dependent active transport system • High concentrations: passive diffusion • Role: Coenzyme for carboxylase enzymes • Deficiency: Rare but can occur during long-term administration of parenteral nutrition Cobalamin (B12) • Absorption • ~15-20% is normally absorbed • 1% is absorbed without intrinsic factor • High dose oral supplementation can be used in pernicious anemia • Binds with intrinsic factor released by the parietal cells of the stomach and absorbed in the distal ileum by selective transport • Dietary Sources: Liver, meat, poultry, fish, milk, cheese and eggs • 2 active forms • Methylcobalamin • Homocysteine → Methionine • Adenosylcobalamin • Methylmalonyl-CoA → Succinyl-CoA • Cobalamins • Methylcobalamin • Adenosylcobalamin • Cyanocobalamin • Hydroxocobalamin Cell Bio 9- Small Intestinal Phase II • Stomach • Gastric acid releases cobalamin from dietary proteins (not required for supplements)—ppi not DI • At low pH cobalamin binds with R-protein (heptocorrin) • Secreted in saliva • Protects cobalamin in the acidic environment • Duodenum • R-protein is digested by trypsin and releases the cobalamin • At neutral pH cobalamin binds with IF (intrinsic factor) • Secreted by parietal cells • Lost in pernicious anemia • 1% is absorbed without IF • High dose oral supplementation can be used in pernicious anemia • Terminal ileum • A highly selective receptor (Cubilin) binds to the cobalamin-IF complex • Absorbed by receptor-mediated endocytosis • Requires pH>5.6 and Ca2+ • Cubilin density increases during pregnancy • Plasma transport • Transcobalamin proteins • TC I: short-term plasma storage depot • TC II: distributes to needed cells • Body contains several years of stored vitamin B12 • TC III: long-term storage or excretion in bile • Deficiency: Megaloblastic anemia • Decreased tetrahydrofolate leads to decreased DNA synthesis • Deficiency: Neurological disorders • Paraesthesia, loss of proprioception and psychotic symptoms • If left untreated can be permanent • Precede anemic effects • Loss of methionine and/or increased methylmalonic acid (MMA) Folic Acid • Synonyms • Folate • Pteroylglutamate (pteroic acid + glutamic acid) • Vitamin B9 • Active form • N5,N10-methylenetetrahydrofolate • Dietary folate • Found as a polyglutamyl conjugate (up to 7 linked glutamates) • Ex. Pte-Glu7 • Green leafy vegetables, egg yolk, yeast and liver • US mandated fortification of all grains • Only pteroylglutamate (Pte-Glu1)can be absorbed • Taken up by a folate carrier protein • Proximal jejunum • Polyglutamyl chains must be broken down • Pteroylpolyglutamate hydrolase (folate conjugase) • Enterocyte luminal membrane • Metabolized to N5-methyltetrahydrofolate (Me-H4-Pte-Glu) in the mucosal cells • Me-H4-Pte-Glu is taken up into the blood Cell Bio 9- Small Intestinal Phase II • • Folic acid required for DNA synthesis Deficiency • Megaloblastic anemia • Congenital neural tube defects (spina bifida) • Recommendation that pregnant women take 0.4mg of folic acid daily • Vitamin B12 required to convert dietary N5-methyltetrafolate to tetrahydrofolate and subsequent conversion to N5,N10-methylenetetrahydrofolate • Folate and B12 deficiency are very similar Calcium • ~40% dietary Ca2+ is absorbed • Luminal transport • Enterocytes in the duodenum absorb Ca2+ by passive diffusion through a Ca2+ channel • Large concentration gradient • Intracellular • Ca2+ complexes with Ca2+–binding protein (calbindin D, CaBP) • Basolateral transport • Ca2+ is excreted from the enterocyte by Ca2+–ATPase pump • Absorption is regulated by circulating Ca2+ plasma levels • 1,25-dihydroxycholecalciferol increases the synthesis of both CaBP and the Ca2+–ATPase pump • Increases Ca2+ absorption Iron • Normally about 5-10% of dietary iron is absorbed duodenum and proximal jejunum • 10-20% in menstruating women • 30-40% in pregnant women • Luminal transport • Heme iron from meat is most efficiently absorbed • Absorbed directly by the heme carrier protein 1 (HCP1) • Inorganic iron salts must be reduced to its ferrous (Fe2+) form to be absorbed • Fe3+ is reduced to Fe2+ by ferrireducttase and ascorbic acid on brush border • Active transport by the divalent metal transporter (DMT1) • Must compete with other metals (Mn2+, Co2+, Cd2+) for the DMT1 • Acidic environment increases absorption • Separates iron from complexes • Give with ascorbic acid (Vitamin C) • ↓ absorption with PPIs, H2 blockers and gastrectomy • Intracellular • Heme Fe3+ released by heme oxygenase and reduced to Fe2+ • Fe2+ is transported across the cell by mobilferrin (mucosal transferrin) • Fe2+ is oxidized to Fe3+ by hephaestin prior to basolateral transport and transport in the plasma • Basolateral transport • Fe3+ leaves the cell via ferroportin 1 (IREG1) protein in the membrane • (IREG1) density is regulated by hepcidin (big regulator of iron homeostasis—inhibits) • ↓ Hepcidin →↑ IREG1 →↑ Fe3+ in the bloodstream • Plasma transport • Bound to transferrin • 2 molecules of Fe3+ • Storage • Iron is primarily stored as ferritin (holds up to 4500 Fe3+ ions) • Stored in macrophages of the liver, spleen and bone and the intestinal mucosal cells • Ferritin in the serum is in equilibrium with stored ferritin • Serum ferritin is an excellent measure of total body iron stores Cell Bio 9- Small Intestinal Phase II • • • • • • Elimination • No specific route of elimination • When enterocytes slough off the ferritin stored in them is lost in the feces • Typically very little iron is lost • Aberrations can lead to anemia (bleeding and menstruation) • Toxicity can result from iron overloading Ex. During iron deficiency • Ferritin mRNA is inhibited by iron regulatory protein 1 (IRP1) • ↑ Fe in the bloodstream • Move out of storage (such as the liver and intestinal enterocytes) • (IREG1) density is regulated by hepcidin • ↓ Hepcidin →↑ IREG1 →↑ Fe3+ in the bloodstream • Moves iron out of enterocytes • ↓ intracellular concentration in the enterocyte to promote absorption • Prevents the loss of stored iron from being lost during enterocyte desquamation Iron homeostasis is regulated by hepcidin • ↑ during Fe excess • ↓ during Fe deficiency • Hepcidin expression is regulated by 3 different proteins • HFE protein • Transferrin receptor 2 (TFR2) • Hemojuvelin (HJV) Hemochromatosis • Iron overload • Fairly common (1:500) • 5-10 X more common in males • Iron is deposited in the liver, pancreas and other organs • Loss of proper hepcidin function and/or expression Type 1: Mutation in HFE gene (80-90%) Rare mutations • Type 2A: Defect in hepcidin • Type 2B: Mutation of the HJV gene • Type 3: Mutation of TRF2 gene • Type 4: Defect in ferroportin (IREG1) • Doesn’t bind hepcidin properly
