Lipid Metabolism.pdf

Biochemistry

1. 1
Lipid Metabolism
6 CO
2+ 6 H
2O + light energy → C
6H
12O
6+ 6 O
2

2. 2
DIGESTION AND ABSORPTION OF LIPIDS

3. 3
DIGESTION AND ABSORPTION OF LIPIDS
98%oftotaldietarylipidsare
triacylglycerols(fatsandoils).Likeall
lipids,triacylglycerols(TAGs)are
insolubleinwater.Hence,water-based
salivaryenzymesinthemouthhave
littleeffectonthem.

4. 4
DIGESTION AND ABSORPTION OF LIPIDS
ThemajorchangethatTAGsundergointhe
stomachisphysicalratherthanchemical.
Thechurningactionofthestomachbreaks
uptriacylglycerolmaterialsintosmall
globules,ordroplets,whichfloatasalayer
abovetheothercomponentsofswallowed
food.Theresultingmaterialiscalled
chyme.

5. 5
DIGESTION AND ABSORPTION OF LIPIDS
Lipiddigestionalsobeginsinthe
stomach.Undertheactionofgastric
lipaseenzymes,hydrolysisofTAGs
occurs.Normally,about10%ofTAGs
undergohydrolysisinthestomach,but
regularconsumptionofahigh-fatdiet
caninducetheproductionofhigher
levelsofgastriclipases.

6. 6
DIGESTION AND ABSORPTION OF LIPIDS
Thearrivalofchymefromthestomach
triggersinthesmallintestine,throughthe
actionofthehormonecholecystokinin,the
releaseofbilestoredinthegallbladder.
Thebile,whichcontainsnoenzymes,acts
asanemulsifier.Colloidparticleformation
throughbileemulsification“solubilizes”
thetriacylglycerolglobules,anddigestion
oftheTAGsresumes.

7. 7
DIGESTION AND ABSORPTION OF LIPIDS
Themajorenzymesinvolvedatthispointare
thepancreaticlipases,whichhydrolyzeester
linkagesbetweentheglycerolandfattyacid
unitsoftheTAGs.Completehydrolysisdoes
notusuallyoccur;onlytwoofthethreefatty
acidunitsareliberated,producinga
monoacylglycerolandtwofreefattyacids.
Occasionally,enzymesremoveallthreefatty
acidunits,leavingafreeglycerolmolecule.

8. 8
DIGESTION AND ABSORPTION OF LIPIDS

9. 9
DIGESTION AND ABSORPTION OF LIPIDS
Withthehelpofbile,thefreefattyacids
andmonoacylglycerolsproducedfrom
hydrolysisarecombinedintotinyspherical
dropletscalledmicelles.Afattyacid
micelleisamicelleinwhichfattyacids
and/ormonoacylglycerolsandsomebile
arepresent.Fattyacidmicellesarevery
smallcomparedtotheoriginal
triacylglycerolglobules,whichcontain
thousandsoftriacylglycerolmolecules.

10. 10
DIGESTION AND ABSORPTION OF LIPIDS
Achylomicronisalipoproteinthat
transportstriacylglycerolsfrom
intestinalcells,viathelymphatic
system,tothebloodstream.
Triacylglycerolsconstitute95%of
thecorelipidspresentina
chylomicron.

11. 11
DIGESTION AND ABSORPTION OF LIPIDS

12. 12
TRIACYLGLYCEROL STORAGE AND MOBILIZATION

13. 13
TRIACYLGLYCEROL STORAGE AND MOBILIZATION
Mostcellsinthebodyhavelimited
capabilityforstorageofTAGs.However,
thisactivityisthemajorfunctionof
specializedcellscalledadipocytes,foundin
adiposetissue.Anadipocyteisa
triacylglycerol-storingcell.Adiposetissueis
tissuethatcontainslargenumbersof
adipocytecells.

14. 14
TRIACYLGLYCEROL STORAGE AND MOBILIZATION

15. 15
TRIACYLGLYCEROL STORAGE AND MOBILIZATION
Theoverallprocessoftappingthebody’s
triacylglycerolenergyreserves(adiposetissue)
forenergyiscalledtriacylglycerolmobilization.
Triacylglycerolmobilizationisthehydrolysisof
triacylglycerolsstoredinadiposetissue,followed
byreleaseintothebloodstreamofthefattyacids
andglycerolsoproduced.Triacylglycerol
mobilizationisanongoingprocess.Onthe
average,about10%oftheTAGsinadiposetissue
arereplaceddailybynewtriacylglycerol
molecules.

16. 16
TRIACYLGLYCEROL STORAGE AND MOBILIZATION
Triacylglycerolenergyreserves(fat
reserves)arethehumanbody’smajor
sourceofstoredenergy.Energy
reservesassociatedwithprotein,
glycogen,andglucosearesmallto
verysmallwhencomparedtofat
reserves.

17. 17
TRIACYLGLYCEROL STORAGE AND MOBILIZATION

18. 18
GLYCEROL METABOLISM

19. 19
GLYCEROL METABOLISM
Duringtriacylglycerolmobilization,one
moleculeofglycerolisproducedforeach
triacylglycerolcompletelyhydrolyzed.
Glycerolmetabolismprimarilyinvolves
processesconsideredintheprevious
chapter.Afterenteringthebloodstream,
glyceroltravelstotheliverorkidneys,
whereitisconverted,inatwo-step
process,todihydroxyacetonephosphate.

20. 20
GLYCEROL METABOLISM
Thefirststepinvolvesphosphorylation
ofaprimaryhydroxylgroupofthe
glycerol.Inthesecondstep,glycerol’s
secondaryalcoholgroup(C-2)is
oxidizedtoaketone.

21. 21
GLYCEROL METABOLISM
Dihydroxyacetonephosphateisan
intermediateinbothglycolysisand
gluconeogenesis.Itcanbeconvertedto
pyruvate,thenacetylCoA,andfinallycarbon
dioxide,oritcanbeusedtoformglucose.
Dihydroxyacetonephosphateformationfrom
glycerolrepresentsthefirstofseveral
situationswewillconsiderwherein
carbohydrateandlipidmetabolismare
connected.

22. 22
OXIDATION OF FATTY ACIDS
Therearethreepartstotheprocessbywhich
fattyacidsarebrokendowntoobtainenergy.
1.Thefattyacidmustbeactivatedbybonding
tocoenzymeA.
2.Thefattyacidmustbetransportedintothe
mitochondrialmatrixbyashuttle
mechanism.
3.Thefattyacidmustberepeatedlyoxidized,
cyclingthroughaseriesoffourreactions,to
produceacetylCoA,FADH2,andNADH.

23. 23
OXIDATION OF FATTY ACIDS
Fatty Acid Activation

24. 24
OXIDATION OF FATTY ACIDS
Fatty Acid Activation

25. 25
OXIDATION OF FATTY ACIDS
Fatty Acid Transport
AcylCoAistoolargetopassthroughthe
innermitochondrialmembranetothe
mitochondrialmatrix,wheretheenzymes
neededforfattyacidoxidationarelocated.

26. 26
OXIDATION OF FATTY ACIDS
Fatty Acid Transport

27. 27
OXIDATION OF FATTY ACIDS
Reactionsofthe-OxidationPathway
The-oxidationpathwayisa
repetitiveseriesoffourbiochemical
reactionsthatdegradesacylCoAto
acetylCoAbyremovingtwocarbon
atomsatatime,withFADH2and
NADHalsobeingproduced.

28. 28
OXIDATION OF FATTY ACIDS
Reactionsofthe-OxidationPathway

29. 29
OXIDATION OF FATTY ACIDS
Reactionsofthe-OxidationPathway

30. 30
OXIDATION OF FATTY ACIDS
Reactionsofthe-OxidationPathway
Step 1: Oxidation (dehydrogenation).

31. 31
OXIDATION OF FATTY ACIDS
Reactionsofthe-OxidationPathway
Step 2. Hydration.

32. 32
OXIDATION OF FATTY ACIDS
Reactionsofthe-OxidationPathway
Step 3: Oxidation (dehydrogenation).

33. 33
OXIDATION OF FATTY ACIDS
Reactionsofthe-OxidationPathway
Step 4: Chain Cleavage.

34. 34
OXIDATION OF FATTY ACIDS

35. 35
OXIDATION OF FATTY ACIDS

36. 36
OXIDATION OF FATTY ACIDS

37. 37
OXIDATION OF FATTY ACIDS
Unsaturated Fatty Acids

38. 38
ATP PRODUCTION FROM FATTY ACID OXIDATION

39. 39
ATP PRODUCTION FROM FATTY ACID OXIDATION

40. 40
ATP PRODUCTION FROM FATTY ACID OXIDATION
Onanequal-massbasis,fattyacidsproduce2.5
timesasmuchenergypergramascarbohydrates
(glucose);thisisshownbythefollowing
calculationinvolving1.00gramofstearicacid
and1.00gramofglucose.

41. 41
ATP PRODUCTION FROM FATTY ACID OXIDATION
Herearesomegeneralizationsabout“fuel”
use:
1.Skeletalmuscleusesglucose(from
glycogen)wheninanactivestate.Ina
restingstate,itusesfattyacids.
2.Cardiacmuscledependsfirstonfatty
acidsandsecondarilyonketonebodies,
glucose,andlactate.

42. 42
ATP PRODUCTION FROM FATTY ACID OXIDATION
Herearesomegeneralizationsabout“fuel”
use:
3.Theliverusesfattyacidsasthepreferred
fuel.
4.Brainfunctionismaintainedbyglucose
andketonebodies.Fattyacidscannotcross
theblood–brainbarrierandthusare
unavailable.

43. 43
KETONE BODIES
Aketonebodyisoneofthreesubstances
(acetoacetate,b-hydroxybutyrate,and
acetone)producedfromacetylCoAwhen
anexcessofacetylCoAfromfattyacid
degradationaccumulatesbecauseof
triacylglycerol–carbohydratemetabolic
imbalances.

44. 44
KETONE BODIES

45. 45
KETONE BODIES
1.Reductionoftheketonegrouppresent
inacetoacetatetoasecondaryalcohol
producesb-hydroxybutyrate.

46. 46
KETONE BODIES
2.Decarboxylationofacetoacetateproduces
acetone.

47. 47
KETONE BODIES
Ketogenesisisthemetabolic
pathwaybywhichketone
bodiesaresynthesizedfrom
acetylCoA.

48. 48
Your Task
Youwilldothistaskwiththree
othermembers.Withyourgroup
mates,brainstormaboutthetopic
assignedtoyouin10minutes.
Assignonemembertoreportand
presentyourgroupsoutputin5
minutes.

49. 49
Your Task
1.Ketogenesis
2.EnergyProductionfromAcetoacetate,and
Ketosis
3.BiosynthesisofFattyAcids:Lipogenesis
4.TheCitrate-MalateShuttleSystem
5.ACPComplexFormation,andChain
Elongation
6.UnsaturatedFattyAcidBiosynthesis,and
RelationshipbetweenLipogenesisandCitric
AcidCycleIntermediates

50. 50
KETONE BODIES
Step 1: First condensation.

51. 51
KETONE BODIES
Step 2: Second condensation.

52. 52
KETONE BODIES
Step 3: Chain cleavage.

53. 53
KETONE BODIES
Step 4: Reduction.

54. 54
KETONE BODIES

55. 55
KETONE BODIES
Energy Production from Acetoacetate
Heartmuscleandtherenalcortexuse
acetoacetateinpreferencetoglucose.The
brainadaptstotheutilizationof
acetoacetatewithstarvationordiabetes.
75%ofthefuelneedsofthebrainare
obtainedfromacetoacetateduring
prolongedstarvation.

56. 56
KETONE BODIES
Energy Production from Acetoacetate
Acetoacetateisactivatedbytransferofa
CoAgroupfromsuccinylCoA(acitricacid
cycleintermediate).Theresulting
acetoacetylCoAisthencleavedtogive
twoacetylCoAmoleculesthatcanenter
thecitricacidcycle.Ineffect,acetoacetate
isawater-soluble,transportableformof
acetylunits.

57. 57
KETONE BODIES

58. 58
KETONE BODIES
Ketosis
Undernormalmetabolicconditions(an
appropriateglucose–fattyacidbalance),the
concentrationofketonebodiesinthebloodis
verylow—about1mg/100mL.Abnormal
metabolicconditions,suchasthosementioned
atthestartofthissection,produceelevated
bloodketonelevels,levels50–100timesgreater
thannormal.Excessaccumulationofketone
bodiesinblood(20mg/100mL)iscalled
ketonemia.

59. 59
KETONE BODIES
Ketosis
Atalevelof70mg/100mL,therenal
thresholdisexceeded,andketonebodies
areexcretedintheurine,aconditioncalled
ketonuria.Theoverallaccumulationof
ketonebodiesinthebloodandurineis
calledketosis.Ketosisisoftendetectable
bythesmellofacetoneonaperson’s
breath;acetoneisveryvolatileandis
excretedthroughthelungs.

60. 60
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
Lipogenesisisthemetabolic
pathwaybywhichfattyacids
aresynthesizedfromacetylCoA.

61. 61
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
The Citrate–Malate Shuttle System

62. 62
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
ACP Complex Formation

63. 63
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
ACP Complex Formation

64. 64
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
ACP Complex Formation

65. 65
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS

66. 66
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
Chain Elongation
Step 1: Condensation.

67. 67
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
Chain Elongation
Step 2: First hydrogenation.

68. 68
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
Chain Elongation
Step 3: Dehydration.

69. 69
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
Chain Elongation
Step 4: Second hydrogenation.

70. 70
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
Chain Elongation

71. 71
BIOSYNTHESIS OF FATTY ACIDS: LIPOGENESIS
Unsaturated Fatty Acid Biosynthesis

72. 72
RELATIONSHIPS BETWEEN LIPOGENESIS AND CITRIC
ACID CYCLE INTERMEDIATES
Thelastfourintermediatesofthecitricacid
cyclebearthefollowingrelationshiptoeach
other.

73. 73
RELATIONSHIPS BETWEEN LIPOGENESIS AND CITRIC
ACID CYCLE INTERMEDIATES
Notetwoimportantcontrastsinthese
compoundsequences:
1.ThecitricacidintermediatesinvolveC4
diacidsandthelipogenesisintermediates
involveC4monoacids.
2.Theorderinwhichthevariousacid
derivativetypesareencounteredin
lipogenelipogenesisisthereverseoftheorder
inwhichtheyareencounteredinthecitricacid
cycle.

74. 74
RELATIONSHIPS BETWEEN LIPOGENESIS AND CITRIC
ACID CYCLE INTERMEDIATES

75. 75
BIOSYNTHESIS OF CHOLESTEROL

76. 76
BIOSYNTHESIS OF CHOLESTEROL

77. 77
BIOSYNTHESIS OF CHOLESTEROL

78. 78
BIOSYNTHESIS OF CHOLESTEROL

79. 79
BIOSYNTHESIS OF CHOLESTEROL

80. 80
BIOSYNTHESIS OF CHOLESTEROL

81. 81
BIOSYNTHESIS OF CHOLESTEROL

82. 82

83. 83

84. 84
RELATIONSHIPS BETWEEN LIPID AND
CARBOHYDRATE METABOLISM
1.Oxidationinthecitricacidcycle.Bothlipids
(fattyacidsandglycerol)andcarbohydrates
(glucose)supplyacetylCoAfortheoperationof
thiscycle.
2.Ketonebodyformation.Thisprocessisof
majorimportancewhenthereisimbalance
betweenlipidandcarbohydratemetabolic
processes.Theimbalanceiscausedby
inadequateglucosemetabolismduringtimesof
adequatelipidmetabolism.

85. 85
RELATIONSHIPS BETWEEN LIPID AND
CARBOHYDRATE METABOLISM
3.Fattyacidbiosynthesis.Thebuildupof
excessacetylCoAwhendietaryintake
exceedsenergyneedsleadstoaccelerated
fattyacidbiosynthesis.
4.Cholesterolbiosynthesis.Aswithfatty
acidbiosynthesis,cholesterolbiosynthesis
occursprimarilywhenthebodyisinan
acetylCoA–richstate.

86. 86
Lipid Metabolism
6 CO
2+ 6 H
2O + light energy → C
6H
12O
6+ 6 O
2