1
Q
Lipid functions
A
- energy source and storage
- major component of cell membranes
- insulation
- precursors to hormones and steroids
- detergents
2
Q
Free fatty acids
A
- carboxylic acid head
- hydrocarbon chain
3
Q
In plasma, 99% of FFAs are bound to
A
albumin
4
Q
Where is high plasma FFA located
A
adipose tissue during fat catabolism
5
Q
Chain lengths and how many carbons
A
- short <6
- medium 8-14
- long >14
6
Q
Most common FA in diet
A
- palmitic acid
- 16:0
7
Q
Miller notation
A
18:2n-6
count from carboxylic acid end
8
Q
Omega notation
A
18:2omega6
count from methyl end
9
Q
In nature, is cis or trans FA found
A
CIS
10
Q
Increased TFA in diet will result in
A
increase body fat stores and membranes
- increased LDL
- increased CVD
- increased inflammation
11
Q
Hydrogenation
A
- adds H, lowers # of dbs
- changes melting point and mouth feel
- biproduct is trans fatty acids (partial hydrogenation)
12
Q
What are glycerolipids
A
- fatty acids linked to glycerol backbone by ester linkages (alcohol + acid)
13
Q
TAG condensation reaction
A
glycerol + 3 fatty acids –> triglyceride + 3 H2O
14
Q
Simple vs complex TAGs
A
- simple: same 3 FAs
- complex: different 3 FAs
15
Q
What increases TG fluidity and stability
A
- decrease chain length
- increase double bonds
16
Q
What are glycerophospholipids
A
- glycerol backbones + FAs position at 1 and 2 + phosphate group at 3
- position 1 is SFA
- position 2 is USFA
- cell membranes
17
Q
5 head group classes of phospholipids
A
- choline
- ethanolamine
- serine
- inositol
- glycerol
18
Q
Functions of PPLs
A
- cell membrane structure
- intracellular messengers
- emulsifiers
19
Q
5 classes of cholesterol steroid hormones
A
- androgens
- estrogens
- progestins
- mineralocorticoids
- glucocorticoids
20
Q
Steroid structure
A
3 rings of cyclohexane + 1 ring of cyclopentane = 4 rings
21
Q
Bile acids
A
- formed from cholesterol
- aid in digestion and absorption of fat and fat-soluble vitamins in intestine
22
Q
What % of ingested fat is in form of TAG
A
90%
23
Q
What % of ingested fat escapes into feces
A
4%
24
Q
Digestion of lipids in mouth
A
- lingual lipase
- hydrolyzes at sn-3
- lipids begin to melt
- very minor
- acid stable
25
Digestion of lipids in stomach
- gastric lipase
- hydrolyzes MCFT on TG especially milk fat
- hydrolyzes at sn-3
- very minor
26
Infants rely more on gastric and lingual lipase because they have very little
- pancreatic lipase
27
Digestion of lipids in small intestine
- presence of chyme triggers release of CCK
- slows down gastric emptying
- stimulates release of bile acids from gall bladder
28
What does pancreatic lipase hydrolyze
- fatty acids at sn-1 and sn-3
29
In small intestine bile converts...
fat --> emulsified fat
30
In small intestine pancreatic lipase converts...
emulsified fat --> 2-monoglyceride + 2 fatty acids
31
Digestion of lipids in large intestine
- some fat and cholesterol trapped in fiber
- exit in feces
32
What does the drug Orlistat do?
- inactivates gastric and pancreatic lipases
- impairs fatty acid absorption
33
Digestion of phospholipids
- mainly phosphatidylcholine
- hydrolyzes at sn-2
- lysophosphatidylcholine + free fatty acid
34
Digestion of cholesterol esters
- pancreatic cholesterol esterase
- hydrolyzes fatty acids on cholesterol esters
35
2 lipid uptake into enterocyte
- passive diffusion
- carrier mediated transporter
36
Passive diffusion
- glycerol, SCFA, MCFA
- micelle delivery: LCFA, cholesterol, lysophosphatidylcholine
37
Carrier mediated transporters
- FABP: fatty acid binding protein
- NPC1L1: cholesterol binding protein
38
Niemann-pick C1 like 1 mechanism
- takes in cholesterol and phytosterols
- separates within the cell
39
Why do phytosterols reduce cholesterol
- inhibits intestinal absorption of cholesterol
- reduce amount of cholesterol in micelles
- gets exported out of intestinal by ABCG5 and ABCG8
40
Reformation enterocyte pathways of lipids
- monoacylglycerol pathway (major)
- glycerol 3-phosphate pathway (minor)
41
Monoacylglycerol pathway
- monoacylglycerol (sn-2) --> MGAT --> diacylglycerol
- diacylglycerol --> DGAT --> TG
- enzymes found in ER membrane
42
Glycerol 3-phosphate pathway
- glycerol 3-phosphate --> GPAT --> diacylglycerol
- diacylglycerol --> DGAT --> TG
- slowest and occurs only when 2-MAG is lacking
43
Reformation of cholesterol ester in enterocyte
cholesterol + fatty acid --> ACAT --> cholesterol ester
44
Glycerol, SCFA, MCFA get transported by...
hepatic portal vein --> liver
45
TG, cholesterol esters, PL get transported by...
packaged into lipoproteins --> chylomicrons --> lymphatic system --> circulation --> uptake of chylomicron remnant by tissues and liver
46
Types of lipoproteins
- chylomicrons (09% lipid)
- VLDL
- IDL
- LDL
- HDL (50% lipid)
47
VLDL site of synthesis, function, and apolipoprotein type
- liver
- transport endogenous cholesterol and TG
- B100
48
IDL site of synthesis, function, and apolipoprotein type
- conversion from VLDL by LPL
- intermediate for LDL
- B100
49
LDL site of synthesis, function, and apolipoprotein type
- conversion from IDL by HL
- deliver cholesterol to tissues
- B100
50
HDL site of synthesis, function, and apolipoprotein type
- liver and intestine
- transport cholesterol to liver
- A1
51
Chylomicrons site of synthesis, function, and apolipoprotein type
- intestine
- transport dietary lipid to circulation
- B48
52
Chylomicron remnants site of synthesis, function, and apolipoprotein type
- conversion by LPL from chylomicrons
- transport dietary lipid to liver
- B48
53
What is LPL
- lipoprotein lipase
- very important enzyme
54
Receptor mediated clearance of lipoproteins
- 90% removed from plasma by LDL receptor
- present on many cell types especially hepatocytes because they all need cholesterol for membrane synthesis
55
LDL receptors regulate...
LDL and chylomicron remnant removal from plasma
56
Cholesterol homeostasis
LDL particle --> binds with LDL receptor in coated pit --> coated vesicle --> endosome --> lysosome --> cholesterol --> ACAT synthesis --> cholesterol ester droplet --> lowers HMG-CoA reductase and lowers LDL receptor synthesis
57
What does body do with excess cholesterol
- reduce cholesterol synthesis
- lower LDL receptor reducing uptake from plasma
58
What does body do with low cholesterol
- increase cholesterol synthesis
- increase LDL receptor increasing uptake from plasma
59
What does statin therapy do in cholesterol homestatsis
- HMG-CoA reductase inhibitor
- reduce cholesterol synthesis
- increase LDL receptor increasing uptake from plasma
- reducing atherosclerosis
60
Endogenous cholesterol
- de novo synthesis 800-1500 mg/day
- hepatic synthesis 50% from VLDL
- intestinal synthesis 30% from chylomicrons
61
Exogenous cholesterol
- animal products in diet 100-300 mg/day
62
What happens when we eat excess cholesterol
- body will just regulate and synthesize less
- consequences are very minimal
63
What does cause hypercholesterolemia?
- high blood cholesterol
- associated with increase dietary intake of saturated fatty acids
- increase risk of atherosclerosis and CVD
64
HDL metabolism
liver makes HDL --> sends to peripheral tissue --> attaches to cholesterol --> goes back to liver --> turned to bile --> excreted in feces
65
Fecal excretion of cholesterol is equal to
- synthesis
66
How much bile acid is reabsorbed/recycled
- up to 90%
67
Fed state of lipoprotein metabolism
intestine --> lymph --> chylomicron --> lipoprotein lipase --> chylomicron remnant --> remaining cholesterol
68
Fasted state of lipoprotein metabolism
liver --> VLDL --> lipoprotein lipase --> LDL --> remaining cholesterol
69
What fuels are used by the liver
- amino acids
- free fatty acids
- lactate
- glycerol
- glucose
- alcohol
70
What fuels are released by the liver
- glucose
- ketone bodies
- lactate
- triacylglycerols
71
What fuels are used by the intestine
- glucose
- glutamine
72
What fuels are released by the intestine
- lactate
- alanine
73
Fatty acid synthesis from acetyl-CoA --> fatty acids requires
- NADPH
- ATP
74
Beta oxidation from fatty acids --> acetyl CoA requires
- FADH2
- NADH
75
2 places fatty acid synthesis occurs via
- de novo lipogenesis
- modification of dietary FAs
76
Rate of de novo lipogenesis determined by
- diet, fed/fast state, energy state, genetics, obesity
- insulin resistance --> DNL is increased!
77
Most healthy individuals have a DNL rate of
less than 5%
78
1st committed step of FA synthesis
- acetyl CoA --> malonyl CoA
- ACC (acetyl-CoA carboxylase)
- activated by citrate
- inhibited by palmitate
79
Acetyl CoA in mitochondria comes from 2 sources
- PDH reaction
- FA oxidation
80
Does high or low blood glucose activate ACC
- high blood glucose
- insulin
- dephosphorylates
81
How is FA synthesis and FA oxidation compartmentalized
- malonyl CoA from FA synthesis inhibits carnitine palmitoyl transferase used in FA oxidation
82
2nd committed step of FA synthesis
- FAS (fatty acid synthase)
- palmitate --> stearate
- elongates chain by 2Cs (even FAs)
83
Sites of FAS regulation
- transcriptional/translational SREBP-1C
- fed state increases FAS expression
- CHO feeding increases FAS expression
- PUFAs feeding decreases FAS expression
84
What does monounsaturated FA synthesis
delta-9 desaturase
85
What does polyunsaturated FA synthesis
delta-12 and delta-15 desaturase
86
FA composition of adipose tissue
- 1/2 oleate (18:1)
- 1/4 palmitate (16:0)
87
Adipose tissue is a combination of 3 sources of FAs
- dietary source (exogenous)
- dietary FAs that have been elongated and desaturated
- de novo synthesized fatty acids (endogenous)
88
2 sources of FAs taken up from circulation
- released by lipolysis of adipose tissue associated with plasma albumin
- generated locally from circulating lipoproteins by lipoprotein lipase found on the endothelium of capillaries
89
3 transporters FAs are taken up by cells
- fatty acid translocase (FAT)
- fatty acid transport proteins (FATPs)
- plasma membrane fatty acid binding protein (FABPpm)
90
What has to happen to the FAs before synthesizes to TG
- re-esterification on the surface of ER
- allows access to ER
91
2 pathways of TG biosynthesis
- monoacylglycerol pathway (major in enterocytes)
- glycerol 3-phosphate pathway (minor in enterocytes and other tissues)
92
Where does TG synthesis occur
- in all tissues that store TG
- muscle, adipose
93
Why is fructose lipogenic
- bypasses glycolysis and insulin regulation
- converts right to glycerol 3-P
- joins with acyl-CoA to TG
- no negative feedback (ATP and citrate)
- no satiety signals
94
2 forms of fat transported in body
- non-esterified or free fatty acids bound to albumin
- triglycerides in lipoproteins and require lipoprotein lipase
95
Where is lipoprotein lipase located
- luminal face on endothelial cell of capillaries
96
What tissue synthesizes and secretes lipoprotein lipase
adipocytes
97
Regulation of LPL in adipocytes
- increases in fed state
- storage
98
Regulation of LPL in muscle cells
- increases in fasting state and exercise
- oxidizes FAs for energy
99
TG in muscle is not released into blood but...
used as an energy source for cell during fasting and prolonged exercise
100
Excessive fat storage in muscle can interfere with
insulin signaling
101
4 steps of fat storage in adipocytes post meal
1. glucose is metabolized to acetyl CoA which can be converted to fatty acids
2. lipoprotein lipase acts on TAG in chylomicrons and free fatty acids and glycerol enters the adipocyte
3. lipoprotein lipase acts on VLDL so TAG, FFA, DG, MG and cholesterol enters the cell
4. pathway favours energy storage as TAG, insulin stimulates lipogenesis
102
Glycerol-3P in liver is from
- glucose
- pyruvate (DHAP intermediate)
- phosphorylated glycerol (lipolysis/TG hydrolysis)
103
Glycerol-3P from adipose tissue is from
- glucose
- pyruvate
- lacks glycerol kinase so glycerol from lipolysis cannot be used for TG synthesis and must be recycled
104
Muscle takes up FFAs and
oxidizes them for energy
105
Liver takes up FFAs and
glycerol for re-utilization
106
Enzyme that catalyzes release of FAs from TG
triacylglycerol hydrolase
ATGL or TGH
107
Enzyme that acts on the surface of TG droplet on sn-1 and sn-3
hormone sensitive lipase
HSL
108
Hormone sensitive lipase (HSL) is regulated by
phosphorylation mechanisms
- by protein kinase A
- epinephrine and glucagon phosphorylates and increases activity
- insulin dephosphorylates and lowers activity
109
Enzyme that acts on sn-2
monoacylglycerol lipase
110
tissues oxidize glucose in ___ state
tissues oxidize FAs in ___ state
- postprandial
- fasted
111
Utilization of glucose decreases when what increases
- acetyl CoA increases
- due to increased TG breakdown
112
What inhibits FA oxidation
- malonyl CoA from ACC reaction
- malonyl CoA levels decrease during fasting thus removing CPT1 inhibition
113
What does CPT1 and CPT2 do
fatty acyl CoAs --> acyl carnitine (CPT1) --> enter mitochondria via carnitine translocase --> converted back to fatty acyl CoAs (CPT2) --> beta-oxidation
114
FAs are primed for oxidation by...
thiokinases in the cytosol
- acyl-CoA synthases on ER activation long chain FAs esterifying them to coenzyme A
- requries ATP
115
Oxidation of odd-chain fatty acids
- similar but end products are acetyl CoA + propionyl CoA
- propionyl CoA can be converted to succinyl CoA
- succinyl CoA enters TCA
116
Oxidation of medium chain fatty acids
- different acyl-CoA dehydrogenases
- diffuses into mitochondria
- does not require CPT1
117
Oxidation of unsaturated fatty acids
- for each double bond, one fatty acyl CoA dehydrogenase reaction is not required
- 2 less ATP per double bond
118
Describe brown adipocytes
- many mitochondria
- uncoupling of oxidative phosphorylation due to UCPs
- thermogenesis
- increases metabolism
119
Acetyl CoA cannot go back into...
glucose
- it has to make ketone bodies instead
120
2 ketoacids in plasma
- acetoacetate
- beta-hydroxybutyrate
121
Describe ketones
- fasting or very low carb diets
- FA oxidation --> acetyl CoA --> ketones
- allows cardiac and skeletal muscle reduce glucose oxidation, preserving plasma glucose for the brain
- does not freely tranverse BBB - upregulated in starvation
122
What tissue cannot utilize ketones
liver
- they synthesize them
- avoids futile cycle
123
Rate of formation of ketone bodies is proportional to
rate of FA oxidation
- coupled process
124
What levels increase in ketosis
- acetone
- smelled on breath
125
Ketolysis occurs in
- non-hepatic tissues
- cytosol
- low SCOT enzyme expression
126
Clinical significance of ketogenesis
- type 1 diabetes - diabetic ketoacidosis
- low glucose, low insulin, high FA oxidation, high glucagon, high acetyl CoA, high ketone, exceeds oxidation capacity, lower pH of blood
127
Why is blood acidification dangerous
- impair ability of hemoglobin to bind oxygen
128
2 major functions of PUFAs
- synthesis of lipid bio mediators
- production of membrane phospholipids (structural and signal transduction)
129
Essential fatty acids
- must be consumed in diet as body does not synthesize it
- linoleic acid (18:2n-6) - omega 6
- alpha linolenic acid (18:3n-3) - omega 3
130
Humans do not have enzyme that add double bonds...
after delta-9 position
131
Conditional essential fatty acids
- body can synthesize but in limited quantities
- eicosapentaenoic acid EPA - omega 3
- docosahexaenoic acid DHA - omega 3
- arachidonic acid AA - omega 6
132
Sources of SFA and MUFAs in body
- diet
- DNL
- elongation and desaturation
133
Sources of 18C PUFAs in body
- ALA and LA only in diet
134
Sources of LC-PUFAS in body
- diet
- elongation and desaturation
- no DNL
135
Eicosanoids are made from __C fatty acids
- 20C and sometimes 22C
- arachidonic acid and eicosapentaenoic acid
136
EFA deficiency is most likely deficient in
LA
- 3-5g/day
137
Clinical symptoms of EFA deficiency
- scaly dermatitis
- failure to grow in children
- suppressed immune function
- impaired reproduction
- degeneration/impaired organ function
138
Clinical symptoms of n-3 specific signs of deficiency
- lower visual acuity
- peripheral neuropathy
139
Can n-6 compensate for n-3 deficiency
- yes but not as efficient
140
What happens to n-6 and n-9 FA during n-3 deficiency
- over produced to over compensate
- arachidonic acid increases producing 22:4n-6, 24:4n-6, and 22:5n-6
- oleic acid increases producing 20:3n-9
- increase triene:tetraene ratio (MA:AA)
- seen in serum phospholipids
141
Last trimester to 18 months, what accumulates in neural tissue
- DHA
142
Pre-natal
- FA transferred through placenta by passive diffusion
- preferential transfer of LC-PUFAs
143
Post-natal
- human break milk contains DHA
- adipose tissue provides greater DHA
144
LC-PUFAs in the brain are ____ conserved and ____ turnover
- highly
- low
145
DHA in retina
- cerebrum, myelin sheath, retinal photoreceptor membranes
146
If n-3 deficient, DHA replaced by...
- DPA (22:5n-6)
- changes retinal physiology, visual acuity, learning ability
147
Sourced of human milk (50% FA)
- maternal body stores
- endogenous synthesis
- uptake from maternal plasma
148
Variation of what FA are in human milk are
- maternal diet
- genetics (FADS1/2)
- lactation stage
- maternal and infant health status
149
Major functions of n-6 FAs
- precursors for signaling molecules (phosphatidylinositols)
- specific ceramides to prevent water loss in skin
- ligands for transcription factors
150
_____ chain metabolites have more potent effects on transcription factor binding
longer
151
3 classes of transcription factors
- PPARs
- liver x receptor
- sterol regulatory element binding protein (SREBP - lipid regulator)
152
SREBP ____ transport to nucleus by PUFAs
inhibited
153
EPA/DHA ____ gene expression levels of pro-inflammatory cytokines
decrease
154
Hypotriglyceridemic effect of fish oil (EPA)
- increased FA uptake by adipose, heart, muscle
- increased b-oxidation, decreased DNL, decreased FA availability in liver
- decreased lipolysis from adipocytes, decreased adipose tissue inflammation, decreased plasma FFAs
- decreased production and clearance of chylomicrons
155
Medication to reduce plasma TG levels as an EPA
- vascepa
156
Biomarkers of EFA intake
- platelet & RBC phospholipids
- adipose tissue (diet has HUGE impact)
- plasma lipids (chylomicrons and VLDLs)
- cheek cell phospholipid DHA and AA - correlated with plasma, RBCs, and diet EFAs - EXCELLENT
157
Phospholipid remodeling
- influenced by diet
- EFAs incorporated into sn-2 position
- continually synthesized and degraded
- need to be changed to make FA available to cell
158
Eicosanoid synthesis
- binding of hormone/cytokine to plasma membrane activates phospholipase A2 (PLA2)
- FAs released from PPLs undergo oxidative reactions (mostly AA)
159
2 main pathways of eicosanoid synthesis
- COX - prostaglandins and thromboxanes via cyclic pathway
- LOX - leukotrienes via linear pathway
160
Eicosanoid activity
- released into extracellular fluid and act locally on adjacent cells
- extremely potent lipid mediators
- inflammatory responses, blood flow/coagulation, pain intensity, fever, reproductive function, smooth muscle contraction/relaxation, gut health/integrity
161
AA derived eicosanoids
- PG, thromboxanes, LTs
- pro inflammatory
162
EPA derived eicosanoisd
- PG, thromboxanes, LTs
- less biologically active
163
EPA and DHA derivates are less
- potent and anti-inflammatory
- and they produce resolvins and protectins (inflammation dampening)
164
EPA competes with
AA for eicosanoid synthesis including membrane incorporation, hydrolysis, oxidative enzymes
165
Acute inflammation
- protective response to get rid of cell injury and repair
- immediate, self-limiting, resolves rapidly, tissue repair
166
Chronic inflammation
- inappropriate activation and sustained duration
- insufficient regulation
- peripheral tissue damage
- chronic diseases - can induce inslin resistance
- EPA supplements can decrease inflammation
167
EPA and DHA dampen inflammatory responses by
- producing less inflammatory eicosanoids
- reducing inflammatory mediators
- producing specialized pro-resolving mediators such as resolvins, protectins, maresins
168
How do dietary lipids modify health
- conversion to bioactive metabolites (eicosanoids and secondary messengers)
- modulation of transcription factor activity and gene expression (ligands)
- alteration of membrane composition and function (fluidity, permeability, protein trafficking, signal transduction, oxidation)
169
Health effects of n-3 FAs
- IBS and rheumatoid arthritis
- Alzheimer's
- MI and stroke incidence, T2D
- cancer cachexia
170
Fat DRIs
- AIs (not for MUFAs or SFAs - non-essential)
- no UL
- AMDR for total fat = 20-35%
SFAs < 10%
171
AI range for n-6 PUFAs
5-10%
172
AI range for n-3 PUFAs
0.6-1.2%
173
AI for n-6:n-3 ratio
5:1
Nutrition 301
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