Lecture 3: Lipids - Structure, Chemistry, and Digestion PDF

PBC 201 Biochemistry I Lipids: Structure, Chemistry & Digestion Ahmed Fawzy El-Yazbi, Bharm, PhD, BCPS Faculty of Pharmacy Overview A heterogenous group of water insoluble substances → compartmentalized Lipids have a broad range...

PBC 201 Biochemistry I Lipids: Structure, Chemistry & Digestion Ahmed Fawzy El-Yazbi, Bharm, PhD, BCPS Faculty of Pharmacy Overview A heterogenous group of water insoluble substances → compartmentalized Lipids have a broad range of functions: A major source of energy in the body (consumption and storage) Form lipid barriers that partition aqueous cell components Fat-soluble vitamins (A,D,E,K) have co-enzyme or hormone-like function Steroid hormones are important in body function and development Lipids are classified into: Simple, Complex and Derived lipids Disorders in lipid metabolism could lead to a variety of diseases including diabetes, atherosclerosis, and obesity Simple Lipids These are esters of fatty acids and different alcoholic components: Oils & fats: esters of glycerol, also known as triacylglycerol (TAG) or triglycerides TAG acts as a fuel store in adipocytes, a thermal insulator, and a protective layer around organs Lipid fuel store lasts much longer than the carbohydrate stores (Liver and muscle glycogen) Cholesteryl esters: esters of cholesterol Waxes: esters of of higher molecular weight alcohols (beeswax & lanolin)  Complex Lipids They contain additional groups: phosphate (phospholipids), carbohydrates (glycolipids), and proteins (lipoproteins) Phospholipids include: Phosphatidyl choline (lecithin): main component of cell membrane, source of choline in the nervous system (precursor of Ach) Phosphatidyl inositol: exclusively found in the inner sheet of cell membrane, broken down in response to stimulation of certain receptors into inositol triphosphate (IP3) and diacylglycerol (DAG), both acting as second messengers  Phospholipids (cont.) Sphingomyelins: Electrical insulators in myelinated nerves, allow rapid propagation of impulses, broken down into ceramide that can act as a signaling molecule, plays an important role in cancers and viral infections Cardiolipins: diphosphatidyl glycerol,major lipid in inner mitochondrial membranes, necessry for mitochondrial function Glycolipids Present in the outer layer of cell membrane Contributes to forming cell surface markers Important for cell recognition in blood transfusion and organ transplantation Lipoproteins Act as the main mode of lipid transport in the blood They vary in density according to the type of their lipid content They include very low-density lipoprotein (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL)  Derived Lipids Obtained by the hydrolysis of simple or complex Plasma Membrane lipids Include faty acids, cholesterol, steroid hormones Phospholipase A2 and fat-soluble vitamins Arachidonic Acid Fatty acids: Lipooxygenase Cyclooxygenase Aliphatic carboxylic acids (RCOOH) Leukotrienes Prostaglandins Major source of dietary lipids Arachidonic acid, which is a fatty acid, is the precursor of eicosanoids (prostaglandins, thromboxane, and leukotrienes) Bronchoconstriction, Inflammation, These are local hormones that play a role in asthma pain, fever inflammation, pain, fever, asthma, blood flow regulation, kidney function, gastric acid secretion, and many other functions Formation of eicosanoids is affected by non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin Fatty Acids (Cont.) According to the length of the aliphatic chain, they can be classified into short (1-6 C), intermediate (8- 14 C), and long chain (16-20 C) fatty acids The carbon chains can be saturated (containing no double bonds) or unsaturated (containing one or more doubnle bonds separated by 3-carbon intervals) Double bonds in naturally occuring fatty acids are all in the cis conformation creating a 120° bend The presence of these bends or kinks help make the lipid packing loser and thus maintain the fluid nature Membrane lipids are mainly formed of unsaturated fatty acids allowing the membrane to be fluid at environmental temperatures to maintian its function Vegetable oils contain a high proportion of unsaturated fatty acids. They can be converted to solid fat by hydrogenation with causes double bond saturation and create trans fats. Saturated and trans- fat consumption increass risk of cardiovascular disease  Carbon atom number in fatty acids Starting at the carboxylic carbon (Delta end) Carboxylic carbon is considered C1 Shows the number of carbons, then the number of double bonds, and then the site of double bond Palmitic acid CH3(CH2)14COOH → 16:0 Oleic acid CH3(CH2)7CH=CH(CH2)7COOH → 18:1Δ9 Linoleic acid CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH → 18:2Δ9, Δ12 Linolenic acid CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7COOH → 18:3Δ9, Δ12, Δ15 Arachidonic acid CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2)3COOH → 20:4Δ5, Δ8, Δ11, Δ14 Starting at the terminal methyl- (CH3) carbon (Omega end) Terminal methyl carbon becomes C1 ⍵ indicates the number of the closest carbon with a double bond Linoleic acid becomes ⍵-6 and linolenic acid becomes ⍵-3 Essential Fatty Acids and Health Human body can produce a variety of fatty acids Human metabolism cannot create double bonds beyond Δ9 carbon Plants can create those kinds of unsaturated fatty acids such as linoleic and linolenic acids These acids become essential fatty acids that should be obtained in the diet from plants that can make them or from animals that fed on these plants ⍵-3 and ⍵-6 unsaturated fatty acids can help reduce blood cholesterol and reduce the risk of coronary artery disease Cholesterol The best known steroid Associated with atherosclerosis development Precursor of steroid hormones Precursor of bile salts needed for lipid digestion Vital component of plasma membrane Steroid Hormones and Fat-soluble Vitamins Steroid hormones include corticosteroids (cortisone) and sex hormones that play important physiological roles Fat-soluble vitamins include vitamins A, D, E, K Vitamin A is necessary for night vision Vitamin D is necessary for bone mineralization Vitamin E is an important anti-oxidant Vitamin K is vital for production of blood clotting factors Lipid Digestion The major components of lipids in diet are triacylglycerol (TAG) 174 15. Die ta ry Lipid Me ta bolis m Cholesterol, cholesterol esters, phospholipids, and Fatty Die tary lipids unestrified fatty acids exist to a lower extent CE, PL, TAG (unc hang e d) H2 O ac ids MOUTH O Chole s te rol Digestion starts in mouth and stomach R C O Cho le s te ryl e s te r (CE) e s te ra s e HO Cho le s te ro l Lingual and gastric lipases act on TAG with short- and S MALL S TOMACH Mo s t o f the CE, PL, TAG, CH2 OC O 2 Fatty CH2 OH INTES TINE medium-chain fatty acids found in milk (Important for and s o me s ho rt- and me dium-c hain fatty ac ids O 2 H2 O ac ids HCOC HC OH suckling infants and patients with pancreatic TO BLOOD PANCREAS Bile s a lts e muls ify, CH2 OP O OCH2 CH2 N+(CH3 )3 Lipa s e s CH2 OP O OCH2 CH2 N+(CH3 )3 insufficiency) a nd pa ncre a tic e nzyme s de gra de die ta ry lipids O- Cho line O- Pho s phatidylc ho line Glyc e rylpho s pho rylc ho line Bile salts are produced in the liver and secreted from the (a pho s pho lipid = PL) CHYLOMICRONS gall bladder to emulsify dietary lipids in the duodenum (LYMPH) Re e s te rifie d) PRIMARY PRODUCTS Fre e fatty ac ids O 2 H2 O 2 Fatty ac ids O CH2 OH (assisted by mechanical mixing due to peristalsis) 2-Mo no ac ylg lyc e ro l Cho le s te ro l Re maining pie c e s o f PL O R 2 C O CH CH2 O C R 1 O P a ncre a tic R 2 C O CH CH2 OH CH2 O C R 3 lipa s e Emulsification increases the surface area of hydrophobic Triac ylg lyc e ro l (TAG) 2-Mo no ac ylg lyc e ro l lipid droplets enhancing the action of pancreatic lipases Fig ure 15.2 Ove rvie w of lipid dige s tion. a cid s ta ble , with pH optimums of pH 4 to pH 6. The s e “a cid lipa se s ” Pancreatic enzymes hydrolyze TAG with long chain fatty pla y a pa rticula rly importa nt role in lipid dige s tion in ne ona te s , for whom milk fa t is the prima ry source of ca lorie s. The y a ls o be come acids, phospholipids, and cholesterol esters producing importa nt dige s tive e nzyme s in individua ls with pa ncre a tic ins uf- ficie ncy s uch a s thos e with cys tic fibros is (CF). Lingua l a nd ga s tric lipa s e s a id the s e pa tie nts in de gra ding TAG mole cule s (e s pe cia lly free fatty acids, 2-monoacylglycerol, glycerol, cholesterol, those with s hort- to me dium-cha in le ngth fa tty a cids) de spite a ne a r or comple te a bs e nce of pa ncre a tic lipa s e (s e e be low). and phospholipids breakdown products 1. Cys tic fibro s is : CF is the mos t common le tha l ge ne tic dis e a s e in Lipid Absorption and Transport II. Dige s tion, Abs orption, S e cre tion, a nd Utiliza tion of Die ta ry Lipids 177 a cyltra ns fe ra s e. Lys ophos pholipids a re re a cyla te d to form phos pho- H C O H2 O Lipid degradation products together with lipid HO H O- 2O C CH O CH O C lipids by a fa mily of a cyltra ns fe ra s e s , a nd chole s te rol is e s te rifie d H O 2 H - O H2 O O C C H C O with a fa tty a cid prima rily by a cyl CoA:chole s te rol a cyltra ns fe ra s e H O C C soluble vitamins and bile salts form mixed (s e e p. 232). [Note : Virtua lly a ll long-cha in fa tty a cids e nte ring the O H C N CH 2 CO O - micelles that help absorption into enterocytes HO e nte rocyte s a re us e d in this fa s hion to form TAGs , phos pholipids , a nd - CH3 CH3 MIXED O chole s te ryl e s te rs. S hort- a nd me dium-cha in le ngth fa tty a cids a re not 2 CO H CH N C O 3 CH 3 H OH MICELLE Short- and medium-chain fatty acids do not conve rte d to the ir CoA de riva tive s a nd a re not re e s te rifie d to 2-mono- C O- O HO CH O C H2 O H CO CH a cylglyce rol. Ins te a d, the y a re re le a s e d into the porta l circula tion, OH CH O 2 H require mixed micelles for absorption H 3 whe re the y a re ca rrie d by s e rum a lbumin to the liver.] 2 OH O O HO C CH 2 CH CH O- CO OH 3 CH CH H HO F. Lipid malabs o rptio n H H O TAG, cholesterol H2O O 2O H C H 2O esters, and phospholipids are 2 N H2 H2 O CO CH H2 O- 2O H2O O H O H2 O O CH 2OH Lipid ma la bs orption, re s ulting in incre a s e d lipid (including the fa t- C O COC H O CH2OH resynthesizeds oluble in vita enterocytes mins a nd e s s e ntia l fa and tty a cidspacked , s e e p. 182)into - in the fe ce s , C O- O lipoproteinain condition aggregates known a s s te a torrhe a , ca n be ca us e d by dis turba nce s lipid dige s tion a nd/orcalled a bs orptionchylomicrons (Figure 15.7). S uch disto turba nce s move through the from lymphatics s e ve ra l conditions , and blood HO ca n re s ult including CF (ca us ing poor dige s - O C O CH 2 CH CH O H 2 OH tion) a nd s hort bowe l s yndrome (ca us ing de cre a s e d a bs orption). H 2O H HO O C stream (Why?) C O- HO H O COC C O OH O C H2 - C O- O Lipid malabsorption (Cystic The a bility fibrosis, of s hort- a nd me dium-chaShort in le ngth O C C OC O Bowel syndrome)faouttty a cids to be ta ke n up by e nte rocyte s with- Symptoms? Treatment? C CH H 2O C H 2O O H C H 2O HO 2 O H H C O CH2 OH COCH H H CH H the a id of mixe d mice lle s ha s ma de the m INTES TINAL 2 OH HO importa nt in die ta ry the ra py for individua ls with MUCOS AL CELL Orlistat ma la bs orption dis orde rs. Fig ure 15.5 Abs orption of lipids conta ine d in G. S e c re tio n o f lipids fro m e nte ro c yte s a mixe d mice lle by a n inte s tina l mucos a l ce ll. [Note : The mice lle Hydro pho bic pre s e nt cha l- Cho le s te ryl e s te rs s ubs trate s : le nge s for the Dig e s tio n o f die tary lipids a re a ls o s ubs tra te s for Pho s pho lipids Triac ylg lyc e ro l Cho le s te ro l is initia te d in the ha s Ac id-s table lip a s e s a id Dig e s tio n o f TAGs LIVER S TOMACH (lin g u a l and (fo und in milk) produce s g a s tric lip a s e s ) in ne o nate BILE a nd continue s in the s tore d in Bic arbo nate re le a s e s bile into P a n c re a tic lip a s e s e cre te s GALLBLADDER S MALL INTES TINE PANCREAS conta ining bile s a lts Ch o le s te ro l e s te ra s e a ide d by P h o s p h o lip a s e A2 s timula te s s timula te s s e cre tion s timula te s s e cre tion of bica rbona te of e nzyme s Enzyme s Cho le c ys to kinin Bile s alts S e c re tin Cho le c ys to kinin Pe ris tals is (fo r e muls ific atio n o f the lipids ) Ho rmo nal Re g ulatio n produce s Ho rmo nal Re g ulatio n Dig e s tive pro duc ts Fre e fa tty a cids (me dium a nd s hort cha in) 2-Monoa cylglyce rol Chole s te rol Fre e fa tty a cids (long cha in) Bile s alts produce s Fat-s o luble vitamins Mixe d mic e lle s fa cilita te a bs orption of die ta ry lipids by INTES TINAL MUCOS AL CELLS (ENTEROCYTES ) a s s e mble a bs orbe d dire ctly into Lipids (with c harac te ris tic pro te in apo B-48) Choles terol, Lipoprotein, and 18 to form Steroid Metabolis m Chylo mic ro ns Co nc e pt c o nne c t s e cre te d into LYMPHATIC S YS TEM which tra ns ports the m to BLOOD which tra ns ports MUS CLE, ADIPOS E TAG-rich chylomicrons to which tra ns ports fa tty a cids whe re lipoprote in lipa s e de gra de s TAG to TIS S UES S UCH AS MUS CLE, ADIPOS E, AND LIVER Fatty ac ids Glyc e ro l me ta bolize d by ta ke n up by MOS T TIS S UES LIVER