NMDF211 Nutritinal Bichemistry Tpic: Energy Systems Bichemistry Part II Sessin: 8 Endeavur Cllege f Natural Health endeavur.edu.au 1
Sessin Objectives Understand the bichemical prcesses and the assciated nutritinal factrs underpinning energy systems in the human bdy: Lipprtein metablism Chlesterl bisynthesis Lipgenesis & Liplysis Clinical issues relating t energy metablism Endeavur Cllege f Natural Health endeavur.edu.au 2
Revisin: Absrptin f Lipids 1. Emulsificatin by bile salts makes lipids mre sluble 2. Pancreatic lipase can then cleave ester bnds frming free fatty acids and mnglycerides that still maintain cntact with bile salts. 3. Tgether bile salts, mnglycerides, free fatty acids and chlesterl frm structures called micelles, which bump up against the intestinal brush brder and fats are taken up int the epithelial cells (Bwen R 2007) Endeavur Cllege f Natural Health endeavur.edu.au 3
Lipid Transprt and Strage Chylmicrns The primary frm f lipprteins frmed frm exgenus lipids Lipprteins ther than chylmicrns transprt endgenus lipids frm tissue t tissue t supply different cells needs Lipprteins differ accrding t rati f lipid t prtein e.g. triacylglycerls, chlesterl, phsphlipids VLDL s cntain higher levels f triacylglycerl (TAG) and less prtein and chlesterl LDL s cntain less TAG, higher prtein and highest chlesterl HDL s cntain lwest TAG, highest prtein and intermediate chlesterl which it delivers back t the liver Endeavur Cllege f Natural Health endeavur.edu.au 4
Lipid Transprt and Strage Aplipprteins The prtein cmpnent f the lipprteins stablise the lipprteins as they circulate in the bld Allws the lipprteins t be recgnised by specific cell receptrs Stimulates certain enzymatic reactins (Grpper, Smith & Grff, 2013) Endeavur Cllege f Natural Health endeavur.edu.au 5
Distributin f Lipids The refrmed lipid derived frm exgenus surces leaves the entercytes (intestinal mucsal cells) largely in the frm f chylmicrns, which then underg cnversin t chylmicrn remnants T sme extent, HDL s can be synthesized within the entercytes and released directly int the mesenteric lymph Lipprteins first appear in the lymphatic vessels f the abdminal regin and then enter the bld stream at a slw rate Entry f chylmicrns int the bld frm the lymphatic system cntinues up t 14 hurs after cnsumptin f a fatty meal Peak bld plasma lipid levels ccur usually 30 mins t 3 hurs after ingestin Chylmicrns and VLDL s are transprted by the bld thrughut all tissues in the bdy Hydrlysis ccurs in certain tissues sites particularly muscle and adipse tissue Extracellular actin n the circulating particles releases free fatty acids and diacylglyerls which are quickly absrbed by the tissue cells Endeavur Cllege f Natural Health endeavur.edu.au 6
Strage f Triglycerides Large, triacylglycerl-laden chylmicrns accunt fr the turbidity (milky appearance) Chylmicrn remnant smaller particle left after liplytic actin that is richer in chlesterl rather than triacylglycerls Chylmicrn remnants are remved frm the bld stream via liver cell endcytsis Nascent VLDL f liver rigin als underges triacylglycerl stripping by lipprtein lipase resulting in the frmatin f a chlesterl rich LDL Within muscles cells, the free fatty acids and thse derived frm hydrlysis f the diacylglycerls are primarily xidised fr energy Aerbically trained muscle des cntain triacylglycerl depsits In adipse tissue the absrbed fatty acids are largely used fr synthesis f triacylglycerls Therefre chylmicrns and VLDL are cleared frm the plasma Refer t Table 5.4 Aplipprteins f Human Plasma Lipprteins in Grpper, Smith and Grff 2013 pg 151 Endeavur Cllege f Natural Health endeavur.edu.au 7
Activity Watch the vide n New Cncepts in Lipprtein metablism t gain a greater understand f the athergenic ptential f varius lipprteins and the rle f membrane aplipprteins. Recmmend viewing starting at 3 minutes int vide. http://www.yutube.cm/watch?v=sw8j1jm4f2g [accessed 26 th Nvember, 2013] Endeavur Cllege f Natural Health endeavur.edu.au 8
Rle f the Liver in Lipid Metablism The liver plays an imprtant rle in the bdy s use f lipids and lipprteins 1. Hepatic synthesis f the bile salts fr digesting and absrbing dietary fats 2. Synthesis f lipids frm nn-lipid precursrs e.g. glucse and amin acids 3. Can take up and catablise exgenus lipids r use these fr resynthesis f ther lipids 4. The synthesis f fatty acids, triacylglycerls, VLDL, HDL, LDL, glycerl, chlesterl, mnaclyglycerls and diacylglycerls. Endeavur Cllege f Natural Health endeavur.edu.au 9
Rle f the Liver in Lipid Metablism (cntd.) Chylmicrn remnant chlesterl and chlesteryl esters may be: a) Cnverted t bile salts and secreted in the bile b) Secreted int the bile as neutral sterl c) Incrprated int VLDL r HDL and released int plasma Endeavur Cllege f Natural Health endeavur.edu.au 10
Rle f the Adipcyte in Lipid Metablism Majr strage site fr triacylglycerls maintained by liplysis and re-esterificatin A single large glbule f fat cnstitutes ver 85% f the adipse cell Each prcess is regulated separately by nutritinal, metablic and hrmnal factrs Adipcyte triacylglycerl can be synthesized frm glucse - influenced by insulin Insulin accelerates the entry f glucse int the adipse cells and increases the availability and uptake f fatty acids by stimulating lipprtein lipase Insulin als inhibits intracellular lipase which hydrlyses stred triacylglycerls Cellular glucse prvides the surce f glycerphsphate fr reesterificatin with the fatty acids t frm triacylglycerls Endeavur Cllege f Natural Health endeavur.edu.au 11
Revisin Questins 1. Which enzyme hydrlyses these particles, allwing the lipids t be released int tissues? 2. Hw d shrt-chain fatty acids travel thrugh circulatin? 3. What is the majr strage site fr triaclyglycerls? 4. What effect can insulin have n adipse tissue? Endeavur Cllege f Natural Health endeavur.edu.au 12
Chlesterl Endeavur Cllege f Natural Health endeavur.edu.au 13
Chlesterl as a Precursr t: 1. Sterids in the bdy gluccrticids 2. Bile salts 3. Sterid sex hrmnes estrgens, andrgens, prgesterne 4. Vitamin D synthesis 5. Structural integrity f cell membranes Endeavur Cllege f Natural Health endeavur.edu.au 14
Lipprteins LDL primary chlesterl carrier Chylmicrns primary TG carrier aplipprtein chlesteryl ester triglyceride phsphlipid a prtein that binds t lipids a cmpund f chlesterl and a fatty acid a cmpund f glycerl and three fatty acids, an rdinary fat mlecule a cmpund f glycerl, tw fatty acids, and an amin alchl eg chline Surce: Intech 2013 Endeavur Cllege f Natural Health endeavur.edu.au 15
Chlesterl Metablism Chlesterl is an extremely imprtant bilgical mlecule that has rles in membrane structure as well as being a precursr fr the synthesis f the sterid hrmnes and bile acids. Bth dietary chlesterl and that synthesised are transprted thrugh the circulatin in lipprtein particles. The same is true f chlesteryl esters, the frm in which chlesterl is stred in cells. Slightly less than half f the chlesterl in the bdy is derived frm bisynthesis. Bisynthesis in the liver accunts fr apprximately 10%, and in the intestines apprximately 15%, f the amunt prduced each day. Chlesterl synthesis ccurs in the cytplasm and micrsmes frm the tw-carbn acetate grup f acetyl-ca. Endeavur Cllege f Natural Health endeavur.edu.au 16
Bisynthesis f Chlesterl The prcess has five majr steps: 1. Acetyl-CAs are cnverted t 3-hydrxy-3- methylglutaryl-ca (HMG-CA) 2. HMG-CA is cnverted t mevalnate 3. Mevalnate is cnverted t the isprene based mlecule, ispentenyl pyrphsphate (IPP), with the cncmitant lss f CO 2 4. IPP is cnverted t squalene 5. Squalene is cnverted t chlesterl. Endeavur Cllege f Natural Health endeavur.edu.au 17
Statins are HMG-CA Reductase inhibitrs Endeavur Cllege f Natural Health endeavur.edu.au 18
Lw Density Lipprteins (LDL) Cnsist f a cre chlesterl surrunded by a layer f phsphlipids and prtein. 20% prtein, 80% lipid (50% is chlesterl) Majr carrier fr endgenusly prduced chlesterl Cells cntain receptrs fr LDL allwing it t be absrbed and used A high bld cncentratin f triglycerides and LDL chlesterl is assciated with increased CVD risk, particularly amng thse individuals with a family histry. The risk f CVD is highly multifactrial and invlves mre than elevated TGs, ttal chlesterl and LDLs. Inflammatin and xidised LDL and genetic bimarkers (including lifestyle) are central t athergenesis. This will be explained further in the fllwing slides. Endeavur Cllege f Natural Health endeavur.edu.au 19
High Density Lipprteins (HDL) Excess cellular chlesterl is transprted back t the liver as HDL chlesterl. 50% prtein, 22% chlesterl ester, 20% phsphlipid, 8% triacylglycerl. HDL transprt f chlesterl frm peripheral cells t liver. In the liver HDL is degraded by lecithin chlesterl transferase in reverse chlesterl transprt using phsphatidylchline. Remving excess chlesterl frm lipid-laden macrphages and peripheral tissue is still cnsidered t be a main ather-prtective functin f HDL. Hwever, several ther prpsed functins f HDL might cntribute t the ptential atherprtective activities (Marsche et al 2013). Regular exercise results in higher HDL levels Endeavur Cllege f Natural Health endeavur.edu.au 20
Antixidant prperties f HDLs In 1992, it was fund that HDL is the majr carrier f lipid hydrperxides in human plasma and that lipid hydrperxides are taken up faster by the liver than nn-xidised lipids suggesting an imprtant rle f HDL in cnquering xidative stress. The anti-xidative prperties f HDL critically invlve HDLassciated enzymes, such as paraxnase 1 (PON1), lipprteinassciated phsphlipase A2 (LpPLA2) and LCAT, which have been reprted t hydrlyse xidised phsphlipids int lysphsphatidylchline (see fllwing slide). In additin, sulphurcntaining amin acids (methinine) f HDL-assciated apprteins are able t detxify redx-active phsphlipid hydrperxides (PLOOH) int redx-inactive phsphlipid hydrxides (PLOH), thereby frming methinine-sulphxides (Marsche et al 2013). Endeavur Cllege f Natural Health endeavur.edu.au 21
Overview f ptential antiathergenic prperties f HDL Surce: Marsche et al 2013 Endeavur Cllege f Natural Health endeavur.edu.au 22
Very Lw Density Lipprtein (VLDL) Changing diet t high carbhydrate frm high fat can result in very-lw density lipprtein chlesterls being prduced Smaller and less dense than chylmicrns. 75% triglycerides, 25% chlesterl Relatively higher in phsphlipids, prtein and chlesterl Primary pathway fr carrying endgenusly manufactured lipids Breakdwns thrugh metablism t intermediate density prteins (45% chlesterl) then t LDL Endeavur Cllege f Natural Health endeavur.edu.au 23
Athergenesis Key event : damage t endthelium pssibly due t Excess lipprtein Hypertensin Diabetes Smking Initially damage is functinal, i.e. endthelium becmes mre permeable t LP L P depsit and accumulate in intima Damaged endthelium allws inflammatry cells (cytkines) int vascular wall Under nrmal cnditins, arterial endthelium repels cells and inhibits bld cltting Endeavur Cllege f Natural Health endeavur.edu.au 24
Athergenesis Macrphages express scavenger receptrs that allw them t engulf and mdify lipprteins and becme fam cells. Lipid laden phagcytes secrete a number f inflammatry mediatrs that amplify inflammatin that: Cntribute t additinal leukcyte accumulatin Smth muscle cell prliferatin Extracellular matrix remdeling Inhibit cllagen prductin Stimulates macrphage express f ptent pr-cagulant tissue factr. Macrphages can cntribute t plaque vulnerability, t rupture, and t frmatin f thrmbi that can precipitate acute crnary events (Libby & Ridker, 2006). Endeavur Cllege f Natural Health endeavur.edu.au 25
Key events: Damage /injury t arterial endthelium Accumulatin f T-cells and mncytes Mncytes enter by endcytsis and are transfrmed int macrphages Cytkines, prteins prduced by mncytes attract circulating LDL s Increased inflammatin Surce: Libby P & Ridker PM et al 2006 Endeavur Cllege f Natural Health endeavur.edu.au 26
Surce: Libby P & Ridker PM et al 2006 Macrphages prduce ROS s which xidise LDL s (Ox-LDL) Ox-LDL s are taken up by macrphages, becme engrged and turn int fam cells Cmplex changes als stimulate expressin f chemkines & grwth factrs Chemkines and grwth factrs stimulate SMC prliferatin and migratin twards vascular lumen Endeavur Cllege f Natural Health endeavur.edu.au 27
The nrmally rdered structure f the arterial wall becmes cmpletely disrupted Accumulatin f cllagen fragments, elastin fragments, lipid laden cells Plaque : lipid cre, fibrus cap Surce: Libby P & Ridker PM et al 2006 Endeavur Cllege f Natural Health endeavur.edu.au 28
Mature athersclertic plaque, als knwn as vulnerable plaque ruptures easily. Thrmbus frms at rupture site. Endthelial cells erde / die near rupture pint Surce: Libby P & Ridker PM et al 2006 Endeavur Cllege f Natural Health endeavur.edu.au 29
Further impacts assciatin between diabetes and increased CVD risk Tur University, 2013 Endeavur Cllege f Natural Health endeavur.edu.au 30
Further impacts assciatin between diabetes and increased CVD risk Tur University, 2013 Endeavur Cllege f Natural Health endeavur.edu.au 31
Questins Name fur bdy functins chlesterl is precursr t? What is the initial prduct needed t synthesize chlesterl? Endeavur Cllege f Natural Health endeavur.edu.au 32
-Oxidatin Cnversin f fatty acids int Acetyl CA Endeavur Cllege f Natural Health endeavur.edu.au 33
-Oxidatin The xidatin f fatty acids in the mitchndria t acetyl CA This reactin is repeated as much as required by the bdy Occurs in the mitchndria after fatty acid activatin Carnitine facilitates transprt f fatty acyl C A t the mitchndria matrix Endeavur Cllege f Natural Health endeavur.edu.au 34
Palmityl CA Acetyl CA FAD Ribflavin B2 dehydrgenase FADH 2 Electrn Transprt Chain Repeated sequence Acyl CA Enyl CA H 2 O hydratase -hydrxyacyl CA -hydrxyacyl CA NAD + Niacin B3 dehydrgenase NADH + + H - Electrn Transprt Chain -ketacyl CA Acetyltransferase CA Pantthenic acid B5 (thilase) Acetyl CA Krebs Cycle Endeavur Cllege f Natural Health endeavur.edu.au 35
What is β-xidatin? Questins What is the carrier mlecule f free fatty acids fr xidatin? Endeavur Cllege f Natural Health endeavur.edu.au 36
Lipgenesis Carbhydrates cnverted t fats fr strage Endeavur Cllege f Natural Health endeavur.edu.au 37
Lipgenesis Since carbhydrates are the majr part f the diet, they must be immediately cnverted int energy, stred as glycgen, r cnverted int fats. A ttal f 55% f the carbhydrates are invlved in the synthesis f fats. The ttal energy cntent f the diet must be balanced with the energy requirements f the human bdy. If excess fds (calries) are ingested beynd the bdy's energy needs, the excess fds (energy) are cnverted int fat. Endeavur Cllege f Natural Health endeavur.edu.au 38
Lipgenesis Lipid metablism is in a cnstant state f dynamic equilibrium. This means that sme lipids are cnstantly being xidized t meet energy needs, while thers are being synthesized and stred. In rats, the average life-time f a single lipid mlecule ranges frm 2 t 10 days. A similar figure prbably applies t human lipid metablism. Endeavur Cllege f Natural Health endeavur.edu.au 39
Lipgenesis The frmatin f lipids frm carbhydrates and prteins. Nt simply the reverse f the fatty acid spiral, but des start with acetyl CA and des build up by the additin f tw carbns units. The synthesis ccurs in the cytplasm in cntrast t the degradatin (xidatin) which ccurs in the mitchndria. Many f the enzymes fr the fatty acid synthesis are rganized int a multi-enzyme cmplex called fatty acid synthetase. Endeavur Cllege f Natural Health endeavur.edu.au 40
Majr pints in Lipgenesis 1. ATP is required 2. The reactins are reductins (additin f H + and use f NADPH) which are the reverse f the xidatins in the fatty acid spiral. 3. ACP (acyl carrier prtein) is the key t fatty acid synthesis a rtating prtein mlecule t which the grwing chain f fatty acids is attached 4. CE (cndensing prtein) cntributed by the amin acid cysteine and aids the grwing f fatty acids Endeavur Cllege f Natural Health endeavur.edu.au 41
Acetyl CA Aceyl ACP Malnyl ACP CO 2 NADPH(H + ) NADP + -ketaceyl-acp -ketacyl-acp synthase -ketacyl-acp synthase -hydrxyacyl-acp H 2 O NADPH(H + ) NADP + Butyryl-ACP Butyryl-CE -hydrxyacyl-acp dehydratase Enyl-ACP reductase Malnyl ACP Butyryl CE Malnyl ACP CO 2 Palmitate 16:0 Endeavur Cllege f Natural Health endeavur.edu.au 42
What is lipgenesis? Questins Where in the cell des this take place? What tw prteins belng t the fatty acid synthase system? Endeavur Cllege f Natural Health endeavur.edu.au 43
Liplysis Breakdwn f fat fr energy Endeavur Cllege f Natural Health endeavur.edu.au 44
Liplysis The breakdwn f triglycerides by lipases is under hrmnal cntrl. The main hrmnes invlved are: 1. Epinepherine (adrenaline) 2. Glucagn 3. Insulin Epinephrine and glucagn activate the breakdwn f liplysis while insulin inhibits fat breakdwn. Triglyceride breakdwn is facilitated by three enzymes: 1. Triacylglycerl lipase 2. Diacyclglycerl lipase 3. Mnacylglycerl lipase Only triacylglycerl lipase is activated by epinephrine Endeavur Cllege f Natural Health endeavur.edu.au 45
Lipgenesis versus Liplysis Lipgenesis (Fatty acids t fats) Occurs in the fed state High bld glucse levels Insulin stimulates glyclysis Pyruvate is then xidised t Acetyl CA Acetyl CA is then available fr Fatty acid synthesis Liplysis (Fats t fatty acids) Occurs in the fasting state, when bld glucse levels are lw Glucagn stimulates liplysis Adrenalin als stimulates fatty acid mbilizatin/liplysis during a stress respnse Liplysis allws energy t be derived frm lipid stres: β-xidatin f fatty acids >> acetyl CA >>> CTC/ETC/OP = ATP Endeavur Cllege f Natural Health endeavur.edu.au 46
Questins Which 3 hrmnes are invlved in liplysis? Hw d their functins differ? What ther effect des insulin have n adipse cells? Endeavur Cllege f Natural Health endeavur.edu.au 47
SUMMARY OF METABOLISM Endeavur Cllege f Natural Health endeavur.edu.au 48
Clinical issues f energy metablism Metablic Syndrme Read the perspective frm yur textbk n Metablic Syndrme, in: Grpper and Smith 6 th Editin, Perspectives: Metablic Syndrme pp 274. In grups f 2-4 discuss and jt dwn the main pints frm this article Cnstruct a shrt synpsis (apprximately 200 wrds), cncluding with any take hme messages Endeavur Cllege f Natural Health endeavur.edu.au 49
Clinical issues f energy metablism Read the fllwing research article (hardcpy als available in sessin readings; Brehm & D Alessi (2008), Weight lss and metablic benefits with diets http://www.nature.cm/nrend/jurnal/v4/n3/pdf/ncpend met0730.pdf Cnsider the 2 diets discussed in this review Lw carbhydrate diet Mediterranean diet Discuss the underlying mechanisms yu can identify which may be cntributing t imprvements in Weight lss Diabetes management Bld lipid prfiles Endeavur Cllege f Natural Health endeavur.edu.au 50
References Brehm, B. J., & D'Alessi, D. A. (2008). Weight lss and metablic benefits with diets f varying fat and carbhydrate cntent: separating the wheat frm the chaff. Nature Clinical Practice Endcrinlgy & Metablism, (3), 140. Grpper, S. S., & Smith, J. L. (2016). Advanced nutritin and human metablism (7th ed.). Belmnt, CA: Wadswrth Cengage Learning. Hey, L., Strain, J. J., & McNulty, H. (2009). Studies f bimarker respnses t interventin with vitamin B-12: a systematic review f randmized cntrlled trials. The American Jurnal f Clinical Nutritin, 89(6), 1981S-1996S. di:10.3945/ajcn.2009.27230c Libby, P., & Ridker, P. M. (2006). Inflammatin and Atherthrmbsis: Frm Ppulatin Bilgy and Bench Research t Clinical Practice. Jurnal Of The American Cllege Of Cardilgy (JACC), 48A33-A46. di:10.1016/j.jacc.2006.08.011 Marks, D. B., Marks, A. D., & Smith, C. M. (1996). Basic medical bichemistry a clinical apprach. Baltimre, MD: Lippinctt Williams & Wilkins. Marsche, G., Saemann, M. D., Heinemann, A., & Hlzer, M. (2013). Inflammatin alters HDL cmpsitin and functin: Implicatins fr HDL-raising therapies. Pharmaclgy And Therapeutics, (3), 341. di:10.1016/j.pharmthera.2012.12.001 Endeavur Cllege f Natural Health endeavur.edu.au 51
Referernces McMurry, J. (1992). Organic chemistry (3rd ed.). Pacific Grve, CA: Brks/Cle Publishing Cmpany. Osiecki, H. (2002). Cancer: A nutritinal/bichemical apprach. Eagle Farm, QLD: Bicncepts Publishing. Rach, J. (2003). Metablism and Nutritin (2nd ed.). Lndn, England: Msby. Shils M. E., Olsn, J. A., Shike, M., & Rss, A. C. (2006). Mdern nutritin in health and disease (9th ed.). Baltimre, MD: Lippinctt Williams & Wilkins. Stker, HS 2014, General, Organic and Bilgical Chemistry, 7 th edn, Brks/Cle, Cengage Learning, Belmnt, CA. Westerterp, K., Smeets, A., Lejeune, M., Wuters-Adriaens, M., & Westerterp- Plantenga, M. (2008). Dietary fat xidatin as a functin f bdy fat. American Jurnal Of Clinical Nutritin, 87(1), 132-135. Yusuf, O., Mhanty, B. D., Martin, S. S., Jshi, P. H., Blaha, M. J., Nasir, K., &... Budff, M. J. (2013). State-f-the-Art Paper: High-Sensitivity C-Reactive Prtein and Cardivascular Disease. A Reslute Belief r an Elusive Link?. Jurnal Of The American Cllege Of Cardilgy, 62397-408. di:10.1016/j.jacc.2013.05.016 Endeavur Cllege f Natural Health endeavur.edu.au 52
COMMONWEALTH OF AUSTRALIA Cpyright Regulatins 1969 WARNING This material has been reprduced and cmmunicated t yu by r n behalf f the Australian Cllege f Natural Medicine Pty Ltd (ACNM) trading as Endeavur Cllege f Natural Health, FIAFitnatin, Cllege f Natural Beauty, Wellnatin - Pursuant Part VB f the Cpyright Act 1968 (the Act). The material in this cmmunicatin may be subject t cpyright under the Act. Any further reprductin r cmmunicatin f this material by yu may be the subject f cpyright prtectin under the Act. D nt remve this ntice. Endeavur Cllege f Natural Health endeavur.edu.au 53