Section 4: Lipids Flashcards
1
Q
Lipids - amphipathic
A
Mostly hydrophobic (hydrocarbon), but with a polar or charged region (carboxylate)
2
Q
Lipids - solubility
A
Usually not water soluble
3
Q
What do lipids form
A
Don’t form large covalent polymers
Tend to form non-covalent higher-order structures
4
Q
Lipids: Formation of non-covalent higher-order structures
A
Sequester the hydrophobic hydrocarbon component(s) from the (polar) aqueous environment
Stabilised by vdW interactions between hydrocarbon part
5
Q
Fatty acids - strength
A
Weak acids - deprotonated at physiological pH (carboxylate form)
6
Q
Fatty acids: Alkyl chains may be…
A
Saturated (fully reduced)
Unsaturated (some C=C):
- monounsaturated: one double bond
- polyunsaturated: many double bonds
7
Q
Fatty acids are a type of _____
A
Lipid
8
Q
Fatty acids: Saturated hydrocarbon chains
A
Can rotate freely about any C-C bond
9
Q
Fatty acids: Unsaturated hydrocarbon chains
A
Can’t rotate around the double bond
Double bond is usually cis, which makes the hydrocarbon chain bend
10
Q
Fatty acids: Number of carbons
A
Most naturally occurring fatty acids have an even no of C atoms because fatty acid synthesis involves adding 2C units
11
Q
Fatty acids: Temperature and C
A
As no of Cs increase, melting point increases for both saturated and unsaturated
12
Q
Fatty acids: Temperature and double bonds
A
Double bonds greatly reduce temp of melting point
13
Q
Essential fatty acids
A
Required for good health and must be ingested, because mammals can’t introduce double bonds in fatty acids beyond carbon 9 and 10
14
Q
Fatty acids: Major physiological roles
A
- Source of hormones and intracellular messengers
- Building blocks of micelles and membranes
- Post-translational modification of proteins
- Fuel
15
Q
Fatty acids and lipids: Micelle
A
Fatty acids are wedge-shaped and tend to form spherical micelles
Polar head groups tend to be larger than their single hydrocarbon chain –> forms curved structure
16
Q
Fatty acids and lipids: Micelles and phospholipids - number of tails
A
Micelle: one tail
Phospholipids: 2 tails
17
Q
Fatty acids and lipids: Phospholipids
A
More cylindrical and pack tgt to form a bilayer structure
18
Q
Biological membranes: Hydrophobic core - length
A
Hydrophobic core ~30Å
Hydrophobic core + interfacial on either side = ~60Å
19
Q
Biological membranes: Interfacial region
A
Polar
Has some lipid headgroups, but also some water molecules - not a sharp boundary
20
Q
Biological membranes: Lipid tails
A
Never perfectly straight
21
Q
Biological membranes: Lipid tails - temp
A
Higher temp = more mobile
22
Q
Biological membranes: How does the cell modify its curvature
A
By putting diff kinds of lipids in the membrane
23
Q
What are found in biological membranes
A
Proteins, channels, sugars
Provide info to cell and ways to pass signals through the membrane
24
Q
Lipid bilayers: States
A
Gel state (below Tm) Liquid crystal state (above Tm)
25
Lipid bilayers: Gel state
Lower temp and more saturated fatty acids
| Hydrocarbon tails are packed tgt in a highly ordered gel state
26
Lipid bilayers: Liquid crystal state
Higher temp an d more unsaturated fatty acids
| Movement of chains become more dynamic and interior of membrane resembles a liquid hydrocarbon
27
Fatty acids: Saturated vs unsaturated
Unsaturated fatty acids bent --> can't pack as well tgt
- fewer vdW can form
- more dynamic / liquid-like
28
Major types of membrane lipids
Glycerophospholipids (glycerol backbone)
Sphingolipids (sphingosine backbone)
Sterols
29
Membrane lipids: Glycerophospholipids
Built on a glycerol backbone
Has a phosphate
2 fatty acid tails (any kind) added onto an O each
30
Membrane lipids: Sphingolipids
Already has a long hydrocarbon chain, so only one more fatty acid needs to be added, which is added onto a N
Head group attached to C1
31
Membrane lipids: Glycerophospholipid - basic structure
```
Phosphate group
Glycerol backbone
R1 and R2 = fatty acids
R3 = head group
2 hydrophobic (fatty acid) chains point into membrane and phosphate group points in opp direction
```
32
Membrane lipids: Glycerophospholipids - phosphatidylserine (PS)
'Eat me' signal
Normally located in inner leaflet of PM
Moves to outer leaflet in apoptosis and attracts phagocytes to consume cell remnants
33
Membrane lipids: Cardiolipin (diphosphatidylglycerol)
4-tailed glycerophospholipid
| Very large head group
34
Glycoglycerolipids are found where
Less common in animal membranes
| Common in plant and bacterial membranes
35
Glycoglycerolipids - structure
Has a glycerol backbone
| Carbohydrate/sugar attached via a glycosidic bond
36
Sphingolipids - where is it found
PM of all eukaryotic cells
| Highest conc in CNS cells
37
Sphingolipids - function
Participate in cell signaling, e.g. regulating cell differentiation, proliferation, programmed cell death
38
Ceramides - basic structure
Also built on sphingosine backbone
39
Sphingolipid vs ceramide
In a ceramide, there isn't really a head group attached to C1, just an OH that's already attached
Whereas sphingolipid has a head group
40
Ganglioside - function
Sit in cell membrane and send out a signal which is recognised by other molecules that then lead to certain functions
41
Ganglioside - structure
Oligosaccharide linked to terminal hydroxyl group of a ceramide via a glucose molecule
Oligosaccharide chain contains at least an acidic sugar or sialic acid
42
Ganglioside - diarrhea
Ganglioside recognition and binding is the first step in the development of at least 2 diarrhea conditions
43
Ganglioside - immune system
Crucial for binding of immune system cells to sites of injury in the inflammation response
44
Gangliosides - Cholera
Pathological condition characterised by severe diarrhea
| Cholera toxin recognises and binds to gangliosides (GM1) to gain access to inside of cell
45
Gangliosides - Enterotoxigenic E. coli
Most common cause of diarrhea
| Like cholera, also produces a toxin that recognises and binds to gangliosides to gain access to cell
46
Cholera and diarrhea
Large V of water are normally secreted into small intestinal lumen, driven by Cl- secretion
Most of this water is absorbed before reaching the large intestine
Diarrhea occurs when secretion of water into intestinal lumen exceeds absorption
47
Cholera and diarrhea - steps
```
Cholera toxins (and other bacterial toxins) bind to gangliosides and strongly activate adenylyl cyclase --> increase in intracellular conc of cAMP
Cl- channels open --> uncontrolled secretion of water (and Na+, K+, HCO3-) into intestinal lumen
Cholera toxin also affects enteric nervous system --> independent stimulus of secretion
```
48
Secretory diarrhea - fasting
Not resolved by fasting
| Often lethal
49
Cholera toxin absorption stimulates / inhibits...
Stimulates cAMP production
Stimulates epithelial Cl- secretion
Inhibits Na+ absorption
50
Cholera - treatment
GM1-coated nanoparticles act as decoys to absorb cholera toxin before it binds to epithelial cells
51
Where is the highest conc of gangliosides found
In nervous system - 6% of lipids
52
Gangliosides - Tay-Sachs disease
Gangliosides in nervous system usually degraded in lysosomes by sequential removal of their terminal sugars
In Tay-Sachs disease, one removal enzyme is missing or deficient --> neurons become swollen with lipid-filled lysosomes
53
Gangliosides - Tay-Sachs disease - symptoms
Severe
Weakness and retarded psycho-motor skills before age 1
Demented and blind by age 2
Usually dead before age 3
54
Lipid composition
Varies between cell types and leaflets
| Allows fine-tuning of membrane properties
55
Lipid membranes - asymmetric
Biological membranes are made of two layers / leaflets
Each leaflet faces a diff environment --> asymmetric
High conc of a lipid on one side = low conc of lipid on other side
56
Lipid membranes: Organelles vs cell membrane
Organelles:
Inner leaflet faces organelle interior
Outer leaflet faces cytoplasm
Cell membrane:
Inner leaflet faces cytoplasm
Outer leaflet faces environment
57
PM typically comprises __ diff lipid types
~60
58
Lipidation of proteins
Allows anchoring to membrane
| Hydrophobic part slots into cell membrane
59
Type of lipid determines...
Protein location
60
Glycolipids are built on...
Either a glycerol backbone or sphingosine backbone
61
Fatty acids: How is fuel/fat stored
Stored as triacylglycerols
| Excess from diet will also be stored here
62
Triacylglycerols AKA...
TAG
Neutral fats
Triglycerides
63
What are triacylglycerols formed from
Ester bonds between carboxyl groups of (same or diff) fatty acids (includes the C=O) and hydroxyl groups of glycerol
64
Fatty acids: Fuel - oxidation
Oxidation of fatty acids released from triacylglycerols produce energy for cellular process
65
Why are triacylglycerols/fats an efficient energy store
They are highly concentrated stores of metabolic energy;
- highly reduced (lots of ability to be oxidised)
- non-polar and so anhydrous
Can carry lots of energy into a small space and weight
66
Define anhydrous
Not much water
67
Fat yields ___x more energy than carbohydrates/proteins
~6.5x
68
What is the major energy storage form in most organisms
Fat
69
3 sources of fatty acids
1. Digestion
2. Adipose tissue
3. Synthesis
70
Sources of fatty acids: Digestion - small intestine
Small intestine contains hydrolytic enzymes from pancreas which can be absorbed into the bloodstream
71
Sources of fatty acids: Digestion - chylomicrons
Transport triacylglycerols through lymph and bloodstream
72
What are bile salts
Emulsifiers
| Amphipathic molecules synthesised from cholesterol in the liver and secreted from gall bladder
73
Transport of fatty acids and other lipids: Lipoprotein particles - function
Emulsify lipids for transport in the blood
74
Transport of fatty acids and other lipids: Lipoprotein particles - structure
Consists of a core of hydrophobic lipids (oil droplet) surrounded by a shell of more polar lipids and proteins
75
Transport of fatty acids and other lipids: Lipoprotein particles - apolipoproteins
Solubilise hydrophobic lipids
Contain cell-targeting signals; helps make sure the fats being transported end up in the right cell
Have a hydrophilic part that points outward
76
Lipoprotein particles - families
```
Chylomicron
(Chylomicron remnant)
VLDL (very low-density lipoprotein)
IDL (intermediate density lipoprotein)
LDL (low-density lipoprotein)
HDL (high-density lipoprotein)
```
77
Lipoprotein density
Increases with increasing protein content (decreasing lipid content) because lipids are less dense than protein
78
Fats - solubility
Not soluble in water, therefore aren't soluble in blood
79
How are fatty acids transported in blood
By lipoprotein particles
80
Density of water
Just under 1
81
Density of lipids vs water/protein
Lipids are generally less dense than protein and water
82
Lipids and proteins - density
More lipids = less dense
| More proteins = more dense
83
Chylomicron remnants
What's left over once the chylomicron has dropped off all its lipids
84
Lipoproteins: Chylomicron
Delivers dietary triacylglycerides to target tissues
85
Lipoproteins: Chylomicron remnant - function
Delivers dietary cholesterol esters left from chylomicron to liver
86
Lipoproteins: VLDL
Transports endogenous triacylglycerides from liver to periphery
87
Lipoproteins: IDL
Remnants of VLDL
88
Lipoproteins: LDL
Major transporter of cholesterol to periphery
89
Lipoproteins: HDL
Picks up cholesterol that's no longer needed from circulation
90
Lipoproteins: Good vs bad cholesterol
```
HDL = good cholesterol
LDL = bad cholesterol
```
91
Most lipids are ingested in the form of _____
Triacylglycerols, so must be degraded to fatty acids for absorption across the intestinal epithelium
92
How are triacylglyceroles in intestinal lumen solubilised
By bile salts
93
Digestion of dietary lipids - steps
1. Cholic acid ionises to give its bile salt
2. Hydrophobic surface of bile salt molecule associates with triacylglycerol, several of which aggregate to form a micelle
3. Hydrophilic surface of bile salts face outward, allowing micelle to associate with pancreatic lipase/colipase
4. Hydrolytic action of lipase frees fatty acids to associate in a much smaller micelle that is absorbed through the intestinal mucosa
94
What is cholic acid
A typical bile acid
| COOH loses H to become COO- (ionised)
95
Triacylglycerides are hydrolysed by...
Pancreatic lipases
96
Digestion of dietary lipids: Pancreatic lipases
Secreted from pancreas
Catalyse hydrolysis of ester bonds between fatty acyl group and glycerol of triacylglycerols
- first hydrolyses off one of the outer fatty acids --> diacylglycerol
- then acts on other outer fatty acid --> monoacylglycerol
Releases 2 free fatty acids
97
Structure of bile salts
Triacylglycerols point in the same direction - this side is the hydrophilic face --> becomes the outer part of micelle
Other side is hydrophobic
98
Monoacylglycerol
Glycerol backbone with one acyl chain attached
99
Where do chylomicrons bind to membrane-bound lipases
At adipose and muscle cells
100
Fatty acids from adipose tissue: Stages of processing
1. Mobilisation
2. Activation and transport
3. Degradation
101
Fatty acids from adipose tissue: Mobilisation
Triacylglycerols are degraded to free fatty acids and glycerol
hydrolysed by hormone-stimulated lipases in adipose tissue
Free fatty acids and glycerol are released from adipose tissue and transported to energy-requiring tissues
102
Fatty acids from adipose tissue: Mobilisation - enzymes
ATGL: adipose triglyceride lipase
triacylglycerol --> diacylglycerol
HSL: hormone-sensitive lipase
diacylglycerol --> monoacylglycerol
MGL: monoacylglycerol lipase
monoacylglycerol --> glycerol
103
Fatty acids from adipose tissue: Mobilisation - what can glycerol be used for
Glycolysis
| Gluconeogenesis
104
Fatty acids from adipose tissue: Mobilisation - what happens to the free fatty acids produced
Transported into the blood plasma and undergoes fatty acid oxidation --> acetyl CoA --CAC--> CO2 + H2O
105
How are fatty acids transported
Since not soluble, they are transported bound to protein serum albumin
106
Serum albumin - function
Bind molecules that are insoluble in water and deliver them to tissues via blood, e.g.
- fatty acids
- hydrophobic hormones
- drugs
- metal ions
107
Uptake of fatty acids - passive?
Originally thought to occur largely by passive diffusion
| Now thought to be mostly facilitated and regulated by proteins
108
Fatty acids from adipose tissue: Activation and transport
Fatty acids arrive in cytosol, but fatty acid degradation occurs in mitochondria so must be activated and transported
109
Fatty acids from adipose tissue: Activation and transport - steps
1. Activation via adenylylation (requires ATP)
2. Transfer to carnitine (replace CoA with carnitine molecule)
Coenzyme A recycled and goes back to activate next fatty acid
3. Transport through mitochondrial inner membrane
4. Reconjugation with CoA
Fatty acyl CoA goes to degradation pathway
110
Fatty acids from adipose tissue: Activation and transport - activated by?
Activated by formation of a thioester linkage to coenzyme A
111
Fatty acids from adipose tissue: Activation and transport - where does this take place
Outer mitochondrial membrane
112
Fatty acids from adipose tissue: Activation and transport - for fats to cross the membrane...
They must be conjugated to carnitine to enter the mitochondrial matrix
113
Fatty acids from adipose tissue: Activation and transport - carnitine acyltransferase I (CPT I)
Bound to outer mitochondrial membrane
| Catalyses transfer of acyl group from coenzyme A to carnitine --> acyl carnitine
114
Fatty acids from adipose tissue: Activation and transport - translocase
Shuttles acyl carnitine across membrane
115
Fatty acids from adipose tissue: Activation and transport - carnitine acyltransferase II (CPT II)
Transfers acyl group back to coenzyme A
116
Is fatty acid degradation anabolic or catabolic
Catabolic - produces e- for oxidative phosphorylation
117
Is fatty acid synthesis anabolic or catabolic
Anabolic
118
What is fatty acid degradation
Degradation of a saturated acyl chain with an even no of C atoms attached to coenzyme A
119
Fatty acid degradation - double bonds / odd no of C atoms
Oxidation of an acyl chain containing double bonds or an odd no of C atoms requires additional steps
120
Fatty acid degradation: Pathway name
β-oxidation pathway
121
Fatty acid degradation: β-oxidation pathway - steps
Recurring sequence of 4 reactions:
1. Oxidation of single bond to double bond. FAD --> FADH2
2. Hydration - addition of water across double bond --> single bond. Forms an alcohol group
3. Oxidation of alcohol to ketone. NAD+ --> NADH + H+
4. Thiolysis - cleavage at β-C to release acetyl-CoA. Adds CoA to activate remainder of acyl chain for further rounds of β-oxidation
122
Fatty acid degradation: In each round of the β-oxidation pathway...
An acyl chain is shortened by 2Cs (in the form of acetyl-CoA)
Acetyl-CoA, NADH and FADH2 are generated
123
Fatty acid degradation: Where does the β-oxidation pathway occur
All reactions happen between α and β carbon of acyl-CoA molecule
α-C is next to carboxyl group, and next one is the β-C
Often the β-C is cleaved
124
Fatty acid degradation: β-oxidation pathway continues until...
There are no Cs left to remove
| e.g. 7 rounds for C16
125
Fatty acid degradation: Fates of acetyl-CoA
Enters CAC or forms ketone bodies
126
Fatty acid degradation: Fates of acetyl-CoA - CAC
If fat and carbohydrate degradation are balanced, acetyl-CoA enters CAC
127
CAC: What does availability of oxaloacetate depend on
On the carbohydrate supply - formed from pyruvate
128
Fatty acid degradation: Fates of acetyl-CoA - Ketone bodies
When more fat than carbohydrate degradation (glycolysis)
| Oxaloacetate is consumed to form glucose via gluconeogenesis
129
Examples of ketone bodies
Acetoacetate
β/D-3-hydroxybutyrate
Acetone
130
When are ketone bodies present in individuals
High levels of ketone bodies often present in blood of untreated diabetics
Also occurs when fasting or on low-carb diets
131
What are ketone bodies
Major fuel source for heart and kidney
*Need to know what a ketone body looks like!*
132
Which structures prefer ketone bodies
Heart muscle and renal cortex
| Brain prefers glucose, but under prolonged starvation can adapt to get 75% of its energy from ketone bodies
133
Energy sources under starvation
After several days,
- slight increase in fatty acids
- decrease in glucose
- large increase in ketone bodies in plasma
134
Palmitoyl-CoA (C16) needs _ rounds of β-oxidation
7
| in 7th cycle, C4 is cleaved into 2 molecules of acetyl CoA
135
Fatty acid degradation - equation
Palmitoyl-CoA + 7FAD + 7NAD+ + 7CoA + 7H2O -->
| 8 acetyl-CoA + 7 FADH2 + 7NADH + 7H+
136
Molecules of ATP produced from fatty acid degradation
~2.5 ATP per NADH
~1.5 ATP per FADH2
~12 ATP per acetyl-CoA
~2 used to activate palmitate (-2)
137
Where does fatty acid synthesis occur
Cytoplasm
138
Fatty acid synthesis: What is acetyl-CoA formed from
From pyruvate in the mitochondria (glycolysis)
139
Mitochondria aren't naturally permeable to...
Acetyl-CoA
| So citrate carries acetyl groups through the inner mitochondrial membrane to cytoplasm for fatty acid synthesis
140
Fatty acid synthesis: Committed step
Starts with carboxylation of acetyl-CoA (2C) to form malonyl-CoA (3C)
Burns 1 ATP - irreversible
Catalysed by acetyl-CoA carboxylase
141
Fatty acid synthesis: Acetyl-CoA Carboxylase 1 and 2
Cytoplasmic enzymes
| Regulates fatty acid synthesis and degradation
142
Fatty acid synthesis: -KS
Ketoacyl synthase
143
Fatty acid synthesis: ACP - structure
Acyl carrier protein
A single polypeptide chain of 77 amino acids
Like a giant version of CoA
144
Fatty acid synthesis: ACP - function
Used to carry around acyl chains
145
ACP and coenzyme A - similarities
Both have a phosphopantethine group - long end of coenzyme A
| Both end in a sulfur that can be joined onto molecules
146
ACP and coenzyme A - differences
Coenzyme A:
Fatty acid degradation
Adenosine phosphate attached
ACP:
Fatty acid synthesis
Protein attached
147
Synthesis pipeline: Fatty acid synthase (FAS)
Giant, multifunctional enzyme complex where all steps in fatty acid synthesis take place
One continuous polypeptide chain folded into domains
Contains enzymes for fatty acid synthesis
Acts as a dimer
148
Synthesis pipeline: Where are fatty acid synthases found
In higher organisms only
149
Fatty acid synthesis: Steps
Fatty acids are elongated by repetition:
1. Condensation of malonyl-ACP and acetyl-KS
2. Reduction of carboxyl group to OH (uses NADPH)
3. Dehydration - forms double bond
4. Reduction (uses NADPH) - double bond becomes single bond
5. Translocation - shuffle growing chain onto KS protein --> ACP is free and cycle repeats
6. C16-acyl-ACP is hydrolysed by a thioesterase (TE) to yield palmitate and ACP
150
Fatty acid synthesis: When does it stop
Elongation cycle is repeated until C16-acyl-ACP is formed
151
Fatty acid synthesis: Thioesterase (TE)
Acts as a ruler to determine fatty acid chain length
152
Most commonly observed fatty acids - no of Cs
C16 and C18
153
Bonds - fully reduced state
All single bonds
154
Fatty acid synthesis: Condensation - cycles
Cycle 1: acetyl-KS + malonyl-ACP
| Cycles 2-6: growing acyl chain-KS + malonyl-ACP
155
To carry out fatty acid synthesis, you need...
2 molecules of NADPH
156
Fatty acid synthesis: Where does NADPH come from
1 mole of NADPH per molecule of acetyl-CoA released from citrate
Additional NADPH required comes from pentose phosphate pathway
157
The accumulation of precursors for fatty acid synthesis involve...
The coordinated use of multiple biochemical pathways
158
Fatty acid synthesis - overall equation
8 acetyl-CoA + 7ATP + 14NADPH + 6H+ -->
| Palmitate + 14NADP+ + 8CoA + 6H2O + 7ADP + 7Pi
159
Major product of fatty acid synthase
Palmitate
160
Elongation and unsaturation: ER
Chain lengthening
| Introduction of double bonds into long-chain acyl-CoAs
161
Longer fatty acids - eukaryotes
Formed by elongation reactions catalysed mainly by enzymes on the cytosolic face of the ER membrane
162
Fatty acid degradation vs synthesis - location
Degradation - mitochondria
| Synthesis - cytosol
163
Fatty acid degradation vs synthesis - carrier of acyl chain
Degradation - coenzyme A
Synthesis - ACP
Both attach the acetyl to a sulfhydryl group
164
Fatty acid degradation vs synthesis - adds/removes _____
Degradation - removes acetyl-CoA
| Synthesis - adds malonyl-CoA
165
Fatty acid degradation vs synthesis - oxidant/reductant
Degradation - oxidant is NAD+/FAD
| Synthesis: reductant is NADPH
166
Fatty acid degradation vs synthesis - starts from
Degradation - saturated fatty acid, any length
| Synthesis - acetyl-CoA
167
Fatty acid degradation vs synthesis - ends with
Degradation - acetyl-CoA
| Synthesis - 16C saturated fatty acid
168
Fatty acid degradation vs synthesis - processing pipeline
Degradation - no processing pipeline
| Synthesis - FAS processing pipeline
169
Fatty acid synthesis: ACC
Acetyl-CoA carboxylase
| Helps regulate fatty acid synthesis
170
Fatty acid synthesis AKA...
Fatty acid metabolism
171
Fatty acid synthesis: Regulation of ACC
Subject to 2 types of allosteric regulation
| Also regulated by a variety of hormones
172
Fatty acid synthesis: ACC - allosteric regulation
Allosteric stimulation by citrate
| Allosteric inhibition by palmitoyl-CoA
173
Fatty acid synthesis: ACC - allosteric regulation by citrate
High citrate when both acetyl-CoA and ATP are abundant - signals raw material and energy are available for fatty acid synthesis
Leads to increased fatty acid synthesis
174
Fatty acid synthesis: ACC - allosteric regulation by palmitoyl-CoA
Abundant when there's an excess of fatty acids
| Leads to decreased fatty acid synthesis
175
Fatty acid synthesis: ACC - hormones
Inhibited by glucagon and epinephrine
| Stimulated by insulin
176
Fatty acid synthesis: ACC - glucagon and epinephrine
Stimulates its phosphorylation by AMP-activated protein --> inhibits ACC
177
Fatty acid synthesis: ACC - insulin
Activates PDH phosphatase --> removes phosphate to activate PDH
Activates citrate lyase to create acetyl-CoA
Stimulates glucose uptake
178
End product of fatty acid synthesis
Palmitoyl CoA
179
Cholesterol - Janus-faced molecule
Described as a Janus-faced molecule because it has both hydrophobic and hydrophilic parts
180
Cholesterol - solubility
Absolute insoluble in water - makes it useful in membranes but also potentially lethal if too much accumulates in one place
181
Cholesterol - structure
Built on a saturated tetracyclic hydrocarbon
| Fused cyclohexane rings all in chair conformation - makes it bulky and rigid compared with other types of lipids
182
Cholesterol tends to _______ lipid membrane structure
Disrupt
183
Cholesterol - amphipathic?
Weakly amphipathic
| Very large hydrophobic part relative to hydrophilic part (polar bit = 1 OH)
184
Roles of cholesterol: Membrane fluidity
Lowers the temp at which the membrane transitions from the gel to liquid crystal phase
185
Roles of cholesterol: Lipid rafts
Cholesterol, sphingolipids and GPI-anchored proteins tend to associate in the membrane to form lipid rafts
Multiple lipid rafts can associate to form 'platforms' where certain proteins will preferentially interact - helps organise membranes
186
GPI
Glycophosphatidylinositol
187
Cholesterol derivatives - examples
Vitamin D
Bile salts
Steroid hormones
188
Cholesterol derivatives: Vitamin D
Group of fat-soluble secosteroids
| Most important forms in humans are vitamin D3 and D2
189
Cholesterol derivatives: Vitamin D - function
Responsible for increasing intestinal absorption of calcium, magnesium and phosphate
Has many other biological effects
190
Cholesterol derivatives: Vitamin D - source
Major natural source is synthesis of cholecalciferol in lower layers of skin epidermis, which is dependent on sun radiation
Only a few foods contain significant amounts of vitamin D
191
Cholesterol derivatives: Vitamin D - not technically a vitamin?
Not essential as can be synthesised in adequate amounts by most mammals if exposed to sufficient sunlight, so not technically a vitamin
192
Cholesterol derivatives: Vitamin D - activation
Activated by 2 hydroxylation steps, the first in the liver and the second in the kidney
193
What are secosteroids
Steroids where part of the ring structure is broken open
194
Cholesterol derivatives: Bile salts
Polar derivatives of cholesterol
| Highly effect detergents
195
Cholesterol derivatives: Steroid hormones
Precursor of potent signalling molecules, including the 5 major classes of steroid hormones
e.g. oestrogen, androgen, glucocorticoids, minerolocorticoids
196
Cholesterol is essential for...
Animal life
197
Cholesterol synthesis - de novo
Can be synthesised de novo (as new);
| Principle sterol synthesised by all animals
198
Cholesterol - plants and eukaryotes
Very little made by plants - make phytosterol instead
| Absent in most prokaryotes
199
Major site of cholesterol synthesis
In mammals, the liver (hepatic cells)
200
Cholesterol synthesis: Where are the C atoms derived from
All 27 C atoms of cholesterol are derived from acetyl-CoA
| Occurs in 3 stages
201
Cholesterol synthesis: Stages
1. Synthesis of isopentenyl pyrophosphate (cytoplasm)
2. Condensation of 6 molecules of isopentenyl pyrophosphate to form squalene (ER)
3. Cyclisation of squalene in an 'astounding reaction' and subsequent 18-step conversion of the tetracyclic product into cholesterol (ER)
202
Cholesterol: Isopentenyl pyrophosphate (IPP)
An inactivated isoprene that is the key building block of cholesterol
203
Cholesterol synthesis - committed step
Part of stage 1
Reduction of HMG-CoA to mevalonate
HMG-CoA reductase is an important control site in cholesterol biosynthesis
204
Cholesterol synthesis: Stage 1 - regulation of HMG CoA reductase
Regulated by controlling:
- rate of synthesis of reductase mRNA (activated by SREBP)
- rate of translation of reductase mRNA
- rate of degradation of reductase
- phosphorylation of reductase (decreases activity)
Regulation at levels of transcription, translation and degradation can later the amount of enzyme in the cell more than 200x
205
Cholesterol: SREBP
Sterol regulatory element-binding protein
| Intracellular sensor that detects low cholesterol levels
206
Cholesterol synthesis: Stage 1 - conversion of mevalonate to isopentenyl
3 consecutive reactions requiring ATP
207
Cholesterol synthesis: Stage 1 - isopentenyl pyrophosphate and dimethylallyl pyrophosphate
Can readily interconvert
208
Cholesterol synthesis: Stage 2
3 molecules of isopentenyl pyrophosphate condense to form farnesyl pyrophosphate
2 molecules of farnesyl pyrophosphate condense to form squalene
209
Cholesterol synthesis: Stage 3
Squalene folds up from an open/linear structure into a ring-like structure
Squalene --> oxidosqualene --3 steps--> lanosterol --19 steps--> cholesterol
210
Cholesterol: Heart disease
Fatty yellow-ish material on arterial walls of patients
211
What is the essential control point of the cholesterol biosynthetic pathway
HMG-CoA reductase
212
Cholesterol synthesis: Managing heart disease
Statin drugs use to treat heart disease target HMG-CoA reductase
Lovastatin and related compounds are potent competitive inhibitors (Ki = 1 nM) of HMG-CoA reductase
213
Control of cholesterol uptake to manage heart disease: Loss of bile salts...
Reduces total cholesterol content body
214
Control of cholesterol uptake to manage heart disease: Bile acid sequestrants
Binders that inhibit the intestinal reabsorption of bile salts
Orally administered +vely charged polymers
Bind -vely charged bile salts
Aren't absorbed themselves
215
Control of cholesterol uptake to manage heart disease: Statins
Resemble mevalonate - structurally and chemically similar
| Mimic both the substrate and product of HMG-CoA reductase
216
Cholesterol: Mevalonate in an enzyme
Folded up into a ring-like structure
217
Cholesterol is carried by __________ as __________
Lipoprotein particles
| Cholesterol esters
218
Cholesterol metabolism: LDL
Cholesterol esters in LDLs are too hydrophobic to pass through the cell membrane, so the LDLs enter the cell through receptor-mediated endocytosis
219
Cholesterol metabolism: LDL - what is engulfed
The entire LDL-receptor complex is engulfed and taken into the cell
220
Cholesterol metabolism: LDL - steps
When LDL gets to cell, it's recognised by LDL receptors in PM
Results in pips where LDL is coated with LDL receptor - the entire thing fuses around the LDL --> endocytic vesicle
Endocytic vesicle fuses with others --> endosome with multiple LDL particles in it - fuses with a lysosome --> lowers pH and breaks up the LDL particles
Releases amino acids, cholesterol, and cholesterol esters
After vesicle releases its contents, it goes back to the PM and waits for the next LDL to arrive
221
What is familial hypercholesterolaemia (FH)
Absence or deficiency of functional receptors for LDL
222
Familial hypercholesterolaemia (FH) - what happens
Cholesterol is deposited in various tissues because of the high conc of LDL cholesterol in the plasma
223
Familial hypercholesterolaemia (FH): Homozygotes
Rare
No functional LDL receptors
Most die of severe coronary heart disease in childhood
224
Familial hypercholesterolaemia (FH): Heterozygote
Common
~Half the normal number of LDL receptors
Pre-mature cardiovascular disease in 30s and 40s
225
Familial hypercholesterolaemia (FH): Mutation
One class of mutations that results in FH generates receptors that are reluctant to give up the LDL cargo
226
What is thermogenesis
Heat generation
227
What is obesity
A medical condition where excess body fat (adipose tissue) has accumulated to an extent that it may have a -ve effect on health
228
What does obesity increase the likelihood of
```
Various diseases and conditions, particularly:
Cardiovascular diseases
Type 2 diabetes
Obstructive sleep apnea
Certain types of cancer
Osteoarthritis
Depression
```
229
What is obesity caused by
Generally caused by a combination of excessive food intake, lack of physical activity and genetic susceptibility
Can also be caused by endocrine and mental disorders, or certain medications
230
Obesity - BMI
Often defined as having a BMI > 30 kg/m^2
Intended for statistical measurement of pops; not a measure of individual body fat, build, or health
Only detects ~50% of cases of obesity
231
Obesity 'pandemic'
Most common nutritional disease in developed countries
| Leading preventable cause of death worldwide
232
Adipose tissue AKA...
Fat
| Body fat
233
Adipose tissue - structure
Loose CT composed mostly of adipocytes
234
Adipose tissue - function
Main role is to store energy in the form of lipids
| Also cushions and insulates the body
235
Types of adipose tissue
White adipose tissue (WAT) - stores energy
| Brown adipose tissue (BAT) - generates body heat
236
Adipocytes AKA...
Lipocytes
| Fat cells
237
What are adipocytes
The primary constituent of adipose tissue
238
Adipocytes are specialised in...
Storing energy as fat
239
Types of adipocytes
White adipocytes - store energy as a single large lipid droplet and have important endocrine functions
Brown adipocytes - store energy in multiple small lipid droplets for use as fuel to generate body heat (thermogenesis)
240
White vs brown adipocytes
```
White adipocyte:
Found in obesity
Low mitochondria density
One large lipid droplet
Store energy
Endocrine functions
```
```
Brown adipocyte:
Anti-obesity
High mitochondria density
Numerous small lipid droplets
Produce heat and dissipate energy through thermogenesis
Endocrine functions
```
241
How much does white adipose tissue contribute to body weight
In healthy, non-overweight humans, white adipose tissue comprises ~20% of body weight in men and ~25% in women
242
White adipose tissue (WAT) - function
Energy storage
Acts as a thermal insulator - helps maintain body temp
Buffer impact
Structural roles
243
Where is white adipose tissue found
Found all over the body
244
White adipocytes - structure
Contain a single large fat droplet, which forces the nucleus to be squeezed into a thin rim at the periphery
245
White adipocytes - contents
Have receptors for insulin, sex hormones, NE, glucocorticoids
Endrocinologically active
246
Where is brown adipose tissue (BAT) found
Especially abundant in new-born humans and hibernating mammals
Also present and metabolically active in adult humans, but prevalence decreases with age
Mostly found around vasculature and organs, and shoulders and upper back
247
Brown adipose tissue (BAT) - main function
Thermoregulation - generates heat by non-shivering thermogenesis
248
Brown adipose tissue (BAT) - capillaries
Contains more capillaries that white fat, which supply the tissue with oxygen and nutrients, and remove/distribute the produced heat throughout the body
249
Brown adipose tissue (BAT) - structure
Contain numerous small droplets of fat
| Contain a much higher no of mitochondria
250
What gives brown adipose tissue their colour
Their large no of (iron-containing) mitochondria
251
Neonates
New-born humans
252
Types of thermogenesis
Shivering thermogenesis
| Non-shivering thermogenesis
253
Shivering thermogenesis
Involuntary contraction of skeletal muscle
254
Shivering thermogenesis - what does it occur in
All mammals exposed to cold will initially shiver to elevate heat production
255
Shivering thermogenesis - hibernating animals
Process by which body temp of hibernating mammals is raised as they emerge from hibernation
256
Shivering thermogenesis - oxygen consumption
In adult humans, it can reach intensities equivalent to 40% of maximum oxygen consumption
257
What does shivering thermogenesis involve
Oxidation of mainly carbohydrates and lipids
258
Shivering thermogenesis - how much can it increase heat production and core temp in humans
Can increase heat production by 3-4x and core temp by ~0.5°C in humans
259
Shivering thermogenesis - efficiency
Inefficient method of heating
- increases convective transfer of body heat away from core by increasing muscle blood flow
- increases convective heat loss to the environment via gross bodily movement (wind chill)
260
Shivering thermogenesis - spontaneity
When cold, it is spontaneous
261
What is non-shivering thermogenesis
Heat production without shivering
262
What is non-shivering thermogenesis carried out by
Brown adipose tissue (BAT)
263
Discovery of non-shivering thermogenesis
Mice in cold (-10°C) food storage rooms
- initially shivered constantly
- later stopped shivering and appeared to thrive
- found to have increased metabolic rate
264
Non-shivering thermogenesis - BAT
Increase in blood flow to BAT in cold conditions
265
Non-shivering thermogenesis - neonates
Brown fat plays an important role in helping neonates avoid hypothermia (a major death risk, especially when pre-mature)
266
Why are infants more susceptible to cold than adults
Higher ratio of body SA to body volume
Higher proportional SA of the head
Little musculature and inability to shiver
Lack of thermal insulation
Inability to move away from cold areas and keep warm
Nervous system not fully developed - doesn't respond quickly/properly to cold
267
What is heat loss and heat production proportional to
Heat loss proportional to body SA
| Heat production proportional to body V
268
Brown adipose tissue (BAT) - neonates
Especially abundant in neonates, especially those born without fur, and hibernating animals
269
How does non-shivering thermogenesis by BAT maintain body temp during cold exposure
Warms blood in surrounding blood vessels before its distribution to the periphery
Ensures an optimal temp for biochemical processes in adjacent organs
270
Mechanism of non-shivering thermogenesis
Energy is instead released as heat by allowing protons to flow down their gradient without producing ATP (proton leak) - ATP synthase is blocked
Uses UCP1
271
UCP1
Uncoupling protein 1
Allows protons to leak across the inner membrane of the mitochondria
Releases stored energy as heat
272
Brown adipocytes - efficiency
Energy inefficient for ATP production
| Energy efficient for heat production
273
Endotherms
Organisms that generate their own heat
274
What cells can uncouple proton transport from ATP production
All cells of endotherms
275
How is BAT specialised for non-shivering thermogenesis
Each cell has more mitochondria than usual
| These mitochondria have a higher-than-normal conc of UCP1 in the inner membrane
276
Brown adipose tissue: NA
Noradrenaline
277
Brown adipose tissue: SNS
Sympathetic nervous system
278
Brown adipose tissue: β1,2,3
β-adrenoceptors
Sit in outer membrane of brown adipocytes
Brown adipocytes mainly have β3, other cells will have other β-adrenoceptors
279
Brown adipose tissue: AC
Adenylyl cyclase
280
Brown adipose tissue: PKA
Protein kianse A
281
Brown adipose tissue: CREB
cAMP regulatory element binding protein
282
Brown adipose tissue: UCP1
Uncoupling protein 1
283
Brown adipose tissue: HSL
Hormone sensitive lipase
284
Brown adipose tissue: TG
Triacylglycerol
285
Brown adipose tissue: FA
Fatty acids
286
Brown adipose tissue: CM
Chylomicrons
287
Brown adipose tissue: LPL
Lipoprotein lipase
288
Activation of brown adipose tissue - steps
1. NA released by SNS acts on β-adrenoceptors, primarily β3
2. This stimulates generation of cAMP by adenylyl cyclase, which activates PKA
3. PKA catalyses phosphorylation of CREB --> increased ucp1 gene expression
4. PKA also catalyses phosphorylation of HSL and perilipin --> activates HSL and dissociates perilipin from lipid droplets --> activates lipolysis of TG stores
5. Released FA stimulate UCP1 and are channeled to the mitochodnria where they enter the β-oxidation pathway and CAC --> ETC --> proton gradient
6. UCP1 dissipates the proton gradient generated by the respiratory chain --> release of energy as heat (thermogenesis)
289
Adipocytes: Perilipin
The protein that covers the intracellular lipid droplets
290
DNP - safety
Not safe - can be deadly
291
DNP - what does it act as
Acts as a proton ionophore to shuttle H+ across cell membranes
Similar to UCP
292
What are kinases
Proteins that phosphorylate other proteins
293
DNP - steps
Dissipates the proton gradient across the mitochondrial membrane
Instead of producing ATP, the energy of the proton gradient is lost as heat
294
More DNP -->
Less efficiency energy production --> metabolic rate increases (and more fat is burned) to compensate
295
BAT: Humans - children
Presence of BAT in newborns and children is well established
296
What was BAT believed to become? What was confirmed recently
Was believed to become more like white adipose tissue in adult humans, but presence and role in thermogenesis only recently confirmed
297
BAT: Modern imaging technology
Detection of BAT was enabled by modern imaging tech:
- PET - metabolic info
- CT - structural info
Combing these overlays functional and anatomical data
298
BAT: Modern imaging technology - PET
Positron emission tomography
| Can identify diff types of metabolic activity
299
BAT: Modern imaging technology - CT
Computed tomography
| Structural info
300
How are types of BAT categorised
Categorised based on cell morphology and location
301
Both types of BAT have...
Small lipid droplets and numerous mitochondria
302
Types of adult BAT
Classic or Constitutive
| Beige or Brite (brown-in-white) or recruitable
303
Adult BAT: Classic / Constitutive - where is it found
Found in highly vascularised deposits, typically between the shoulder blades, surrounding the kidneys, neck, and supraclavicular area, and along the spinal cord
304
Adult BAT: Classic / Constitutive - lipid droplets
Smaller of the two types with numerous small lipid droplets
305
Adult BAT: Beige / Brite / Recruitable - where is it found
Interspersed with white adipocytes in WAT
| Develops from white adipocytes after stimulation by SNS (noradrenalin)
306
Adult BAT: Beige / Brite / Recruitable - lipid droplets
Greater variability in lipid droplet size and a greater proportion of lipid droplets to mitochondria than BAT --> beige appearance
307
Adult BAT: Beige / Brite / Recruitable - when is it found
Recruited when you need it to generate heat
308
Adult BAT: Classic / Constitutive - when is it found
Always occurring
309
Browning of WAT to form BAT - reversibility
Adaptive and reversible response to environmental challenges
310
Adult BAT: Beige / Brite / Recruitable - what is it rich in
Rich in UCP1 and mitochondria
311
What factors cause browning / whitening of adipocytes
White adipocytes --browning--> beige adipocytes:
- cold
- β3-agonism
Beige adipocytes --whitening--> white adipocytes:
- thermoneutrality
- high-fat diet (HFD)
312
Almost everything used to combat obesity is ________
Reversible
313
Browning of WAT: Evidence in rodents - newborn lacking BAT
Newborn (neonate) mice lacking BAT (knockout, K) have reduced body temp
314
Browning of WAT: Evidence in rodents - adult mice lacking BAT
Have normal body temp at 22°C
Adult slowly to prolonged cold temp
Exhibit increased browning of some types of WAT for thermoregulation
315
Is conversion of WAT to BAT in rodents a short or long term process
Allows mice to have normal body temp at colder temps over a longer time - longer term
316
Browning of WAT: Evidence in rodents - UCP
Control mice with plenty of BAT don't have any UCP in their WAT
Knockout mice have lots of UCP expressed in sWAT
Suggests WAT is being converted to BAT to generate heat
317
What is sWAT
Subcutaneous white adipose tissue
318
What does NA stimulate conversion of
WAT to BAT
319
Browning of WAT: Evidence in rodents - NA (NE)
Knockout mice have higher levels of NA --> suggests it is needed to turn WAT into BAT
320
Browning of WAT: Evidence in rodents - α-tubulin
A protein found in all cells
| Control to make sure there's some cellular protein loaded onto the gel
321
Browning of WAT: Evidence in rodents - No BAT gives ____ skin temp, about ___ of normal
Reduced
| 94%
322
Browning of WAT: Evidence in rodents - infrared image
Tells us how much heat was being given off the mice
323
Browning of WAT in rodents by 'hot' and cold therapy - β-AR
Extensive efforts have been made to pharmacologically activate BAT thermogenesis using synthetic β-adrenergic receptor (β-AR) agonists
324
Browning of WAT in rodents by 'hot' and cold therapy - examples
Chilli peppers (capsinoids, non-pungent capsaicin analogues) and mild cold exposure
325
Browning of WAT in rodents by 'hot' and cold therapy - experiment
Mice were fed a high fat diet supplemented with capsaicin analogues under mild cold conditions for 8 weeks
This synergistically suppressed body weight gain and increased energy expenditure on a high-fat diet
326
Browning of WAT in rodents by 'hot' and cold therapy - steps
Cold sensation registered on skin and transmitted to WAT deposits through SNS and β-AR
Capsinoids bind to capsinoid receptor in gut
327
Browning of WAT in rodents by 'hot' and cold therapy - capsinoid receptor
Transmembrane receptor
| Activation of it can produce a painful burning sensation
328
Browning of WAT in rodents by 'hot' and cold therapy - BAT adipogenesis is synergistically stimulated through...
Increased β-AR expression
| Stabilsiation of transcription factor PRDM16, a major transcriptional regulator of BAT development
329
Cachexia - symptoms
Inflammation
Body weight loss
Atrophy of adipose tissue
Skeletal muscle wasting
330
Where is cachexia observed
In a majority of cancer patients with advanced disease
Also at the end stage of various other morbidities, e.g. infectious diseases (AIDS) or chronic conditions (heart failure)
331
Cachexia is responsible for ___ of total deaths from cancer
20%
332
What does cachexia involve
Systemic inflammation and IL-6, both of which induce and sustain WAT browning
333
Cachexia: IL-6
Stimulates the adrenal gland to reduce catecholeamines --> induces NA
334
Cancer cachexia patients stain positive for...
UCP1 in WAT
335
What seems like a promising approach to ameliorate cachexia in cancer patients
Inhibition of WAT browning, as it stops the the high energy expenditure
336
Thermogenic capactiy
Ability of the body to produce heat
337
WAT - burn trauma
Browning of WAT occurs in humans following burn trauma
338
Browning of WAT in humans: Burn trauma - what is it
Severe and prolonged adrenergic stress
339
Browning of WAT in humans: Burn trauma - what does it result in
Prolonged elevation of circulating NA levels for several weeks post-injury
340
Browning of WAT in humans: Burn trauma - what does it increase
Resting energy expenditure
Expression of UCP1
No of mitochondria
Oxidative capacity
341
Browning of WAT in humans: Burn trauma - what could it reflect
Need for increased thermogenesis to maintain normal body temp following loss of insulating skin barrier
342
Browning of WAT in humans: Burn trauma - NA
Large 10x increase in circulating NA - persists for several weeks post-burn
Much greater than the transient increases (1.5x) in NA levels seen in patients exposed to chronic cold
This 'catecholaminergic' surge associated with larger burns may contribute to browning of WAT
343
Artificially stimulating and controlling browning in humans - experiment
Healthy young male subjects:
- some had BAT already (+), others didn't (-)
- BAT+ and BAT- subjects randomly assigned to 2 groups
- one group exposed to cold at 19°C for 2 hours
- other group at 27°C for 2 hours
344
Artificially stimulating and controlling browning in humans - experiment results
Exposure to lower temp increased energy expenditure
| Activation of pre-existing BAT but no browning of WAT - no new BAT
345
Artificially stimulating and controlling browning in humans - cold vs capsinoid exposure
Prolonged cold exposure increases browning of WAT
| Prolonged capsinoid treatment increases browning of WAT
346
Artificially stimulating and controlling browning in humans: Cold vs capsinoid exposure - interpreting experiments
Must be careful interpreting these experiments because don't know how much of these results is because of the experiment and how much is because of the diff people
347
Artificially stimulating and controlling browning in humans: Bile acids
```
Can activate TGR5 -->
Increases cAMP conc -->
Activates deiodinase enzyme D2 -->
Produces active thyroid hormone -->
Converts T4 into T3 -->
Increased UCP1 and BAT activity
```
348
TGR5
A thyroid G-protein coupled receptor
349
Artificially stimulating and controlling browning in humans: Bile acids - experiment
12 healthy females treated for 2 days
| Orally took a bile acid (CDCA)
350
Artificially stimulating and controlling browning in humans: Bile acids - experiment results
Small increase in whole body energy expenditure and BAT activity, but not as large as increase under cold conditions
No browning of WAT
Probably not very useful
351
Cold-induced WAT browning - glucose
Increases rate of glucose uptake by BAT - more than insulin stimulates glucose uptake by skeletal muscle
352
Cold-induced WAT browning - cold exposure increased ... in existing BAT of mice
Both glucose and fatty acid uptake
353
Cold-induced WAT browning - cold and capsinoid exposure increases...
Conversion of WAT to BAT
| Correlated with increased body energy expenditure
