1
Q
characteristics of lipids
A
- soluble in organic solvents (e.g ether, chloroform, acetone)
- wide variety of structures and functions
- source of energy
- major component of cell and organelle membranes
2
Q
lipid functions (8)
A
- concentrated energy source (9kcal/g)
- palatability of food and increase satiety
- source of essential fatty acids (omega-3 and 6)
- source of fat-soluble vitamins (A, D, E and K)
- necessary for growth and development
- important precursors for production of hormones
- affect inflammation and blood clotting
- key roles in disease development (atherosclerosis, diabetes, obesity, etc)
3
Q
saturated fatty acids
A
- maximum number of hydrogens
- only single bonds
- butyric acid: in the stomach - from bacteria
- palmitic acid: most common that we eat
4
Q
monounsaturated fatty acid
A
- missing hydrogens
- only one double bond
- oleic acid: 18:1 cis-configuration
- elaidic acid: 18:1 trans-configuration
5
Q
polyunsaturated fatty acid
A
- missing hydrogens
- multiple double bonds
- the more double bonds, the more kinked the structure, the more fluid the membrane
6
Q
omega system nomenclature
A
- numbering starts from the methyl (CH3) end
e.g. 18:2 n-6 OR w-6
18 = number of carbons
2 = number of double bonds
6 = location of 1st double bond
7
Q
delta system nomenclature
A
- numbering starts from the carboxyl end (COOH)
- e.g. 18:2 delta^9,12
18 = number of carbons
2 = number of double bonds
9,12 = position of double bonds
8
Q
essential fatty acid discovery
A
Barr experiment: fed rats diets that were completely fat-free and noticed stunted growth, lost fur, inflamed and scaly tails
- Infant experiment: fed infants diets with <0.1% linoleic acid and noticed poor growth and thickened dry skin
9
Q
what are the essential fatty acids?
A
linoleic acid (18:2 n-6) aka. omega-6
alpha linoleic acid (18:3 n-3) aka. omega-3
- humans lack the enzymes necessary to insert DBs beyond the delta-9 position of a fatty acid therefore we have to get from food we consume (abundant in plants)
- the delta-12 and 15 FAs are produced in plants
10
Q
signs of omega-6 deficiency
A
skin: dermatitis (water leaves the membrane, leads to lost moisture and potential infection)
growth: decreases
reproductive maturity: decreases
CNS and retinal development are OK
11
Q
signs of omega-3 deficiency
A
skin, growth and reproduction are OK
CNS development: IQ decreases
Retinal development: visual acuity decreases
12
Q
who is most susceptible to EFA deficiency
A
infants: formula isn’t properly designed
hospitalized patients: fluid diets don’t contain proper amounts of EFAs
13
Q
how much EFAs in our diet do we need to avoid deficiency?
A
omega-6 = 2-3% of energy in diet
omega-3 = 1% of energy in diet
14
Q
why can an imbalance of omega3 and 6 cause problems
A
n-6 is used to make pro-inflammatory molecules
n-3 is used to make anti-inflammatory molecules
15
Q
what makes pets susceptible to EFA deficiency?
A
Dogs: can convert ALA to EPA but not DHA which they require in their diet
Cats: lack the enzymes to make LCFA which they require in their diet
16
Q
EFA desaturation and elongation
A
- converts ALA and LA to downstream metabolites (humans are not good at this)
- desaturation removes hydrogen (creates DB)
- elongation adds 2 carbons
17
Q
how does linoleic acid (18:2 n-6) lead to pro-inflammatory eicosanoid production?
A
- linoleic acid -> gamma-linoleic acid (via delta-6 desaturase)
- -> dihomo-gamma-linoleic acid (via elongase 5)
- -> arachidonic acid (via delta-5 desaturase)
18
Q
how does alpha-linoleic acid (18:3 n-3) lead to anti-inflammatory eicosanoid production?
A
- a-linoleic acid -> stearidonic acid (via delta-6 desaturase)
- -> eicosatetraenoic acid (via elongase-5)
- eicosapentaenoic acid (via delta-5 desaturase)
- EPA can be further converted to DHA if needed
19
Q
linoleic acid metabolism
A
- new double bond added at 6th position of carbon backbone from carboxyl end
- two carbons added (from malonyl CoA) at carboxyl end
- new double bond added at 5th position from carboxyl end
*always do modifications from carboxyl end
20
Q
what are eicosanoids?
A
- metabolites of 20-carbon FAs (mostly derived from AAs and EPAs)
- have rapid degradation - act where they were made
- produced by most cells
- hormone-like function, but act locally (don’t travel)
- role in inflammation, platelet aggregation, blood pressure, etc.
- common ones: PGD2, TXA2, LTE4
21
Q
how do we produce eicosanoids?
A
- start with a phospholipid
- phospholipase A2 removes the omega-6 chain to give arachidonic acid (PLA2 can be inhibited by corticosteroids)
- 1 of 3 pathways happens from here…
1. cyclooxygenase pathway: uses COX enzyme, can be inhibited by aspirin
2. Epoxidase pathway: uses CYP540 enzymes
3. Lipoxygenase pathway: uses LOX enzyme
22
Q
What are triglycerides (TAGs)?
A
- major dietary and storage lipid
- critical in lipogenesis, lipolysis and are transported in lipoproteins
- contains a glycerol backbone + 3 fatty acid tails ( connected by ester bonds
- can have mono, di, or triacylglycerol structures
- fatty acid composition determines physicochemical properties
23
Q
what are phospholipids?
A
- more polar than TAGs - hydrophilic phosphate head group
- major component of membranes and anchor membrane proteins
- source of physiologically active fatty acids for eicosanoid synthesis
- intracellular signalling
24
Q
what are Sterols?
A
- steroid alcohols
- either free or esterified with a fatty acid (cholesterol ester)
- sources of cholesterol (diet ~40%, endogenous ~60%)
- primary functions: essential components of membranes, steroid sex hormone production, bile acid production, vitamin D synthesis
25
lipid digestion: mouth
lingual lipase is continuously secreted and starts to digest TAGs
26
lipid digestion: stomach
- gastric lipase is continuously secreted and targets TAGs
- lipase is stable at low pH (stomach acid)
27
lipid digestion: liver and gallblader
- liver makes bile acids (salts)
- gallbladder stores bile salts
- gallbladder releases bile, triggered by hormones
28
lipid digestion: small intestine
- pancreatic enzymes include pancreatic lipase, cholesterol and esterase to digest lipids
29
What are mixed micelles?
- small, spherical complexes containing lipids, lipid digestion products and bile salts
- digested lipids are emulsified by conjugate bile acids
- can access spaced between microvilli in the intestine
- carrier-mediated transporters have been identified to bring digested fat to membranes and take them up
30
what are bile salts?
- bile salts are bile acids that are conjugated with taurine or glycine in the liver
- deconjugated by gut bacteria, and bile acids are reabsorbed and recycled through enterohepatic circulation
- emulsify lipids into smaller units which aid pancreatic lipase in digesting them
31
Enteropathic circulation of bile acids
- bile acids are made from cholesterol in the liver and then turned into bile salts
- bile salts are stored in the gallbladder and travel through the intestine
- ~5% of bile acids are lost in feces and the remaining 95% of bile acids are reabsorbed and recycles back to the liver
*soluble fibres reduce the efficiency of enterohepatic circulation by holding onto bile acids which are then secreted in feces - reduce cholesterol levels by binding them
32
lipid absorption at the intestinal lumen
- mixed micelles bring all the lipid products to the intestinal membrane (except SCFAs)
- pancreatic lipase acts on TAGs at the sn-1 and sn-3 position to give 2MAGs and a FFA
- cholesterol esterase acts on cholesterol esters to give a cholesterol and FFA
- phospholipase acts on phospholipids to give lysoP and FFA
- all lipid products from mixed micelles that were broken down are reassembled at the ER and packaged into chylomicrons (protein coating)
- chylomicrons are exocytosed out of the intestine and into the circulation
- SCFAs are an exception and diffuse through the membrane and then directly into the blood
33
Lipid transport
- lipids move through the circulation in lipoproteins
- lipoproteins are classified by ratio of lipid-to-protein (affects density) and specific Apo content (which affects receptor interactions)
34
classification of lipoproteins
Chylomicron: high lipid and low protein, ApoB-48 C and E, only peptide from the intestine
VLDL: high lipid and low protein, ApoB-100 C and E, made in the liver
VLDL becomes IDL becomes LDL
LDL: relative to VLDL, protein to lipid ratio increases, "bad cholesterol"
HDL: Low lipid and high protein, ApoA, "good cholesterol"
35
good cholesterol vs bad cholesterol
bad = LDL, good = HDL
- cholesterol itself is identical but lipoproteins are doing different things
- HDL picks up cholesterol around the body and moves it back to liver to be cleared
- LDL contains 60% of blood cholesterol in a fasting subject
36
What is the rate of chylomicron circulation?
- increase circulation of lipids after a meal
- enter circulation at a slow rate (peaks between 30min-3hrs after eating)
- enter the lymphatic system first, the blood - dietary lipids are available to adipose and muscle before liver
37
What does lipoprotein lipase do?
- located on the surface of endothelial cells lining small blood vessels and capillaries
- not expressed in the liver, but is in adipose and muscle
- activated by ApoC
- hydrolyzes the TAG in chylomicrons into 2-MAG +2 fatty acids which when TAG depleted are referred to as "chylomicron remnant"
38
Chylomicron Remnants
- TAG depleted chylomicrons
- removed from the circulation through ApoE-mediated interactions with a receptor in the liver
39
lipoproteins from the liver vs the small intestine
small intestine
- produce chylomicrons
- ApoC activates LPL which hydrolyzed the TAGs
- when TAG depleted left with chylomicron remnant
liver
- produces HDL and VLDL
- ApoC in VLDL activates LPL and hydrolyzes TAGs
- left with TAG-depleted LDL
40
Low-density lipoprotein (LDL)
- VLDL is released from the liver and is the main transporter of endogenous TAGs
- LPL is activated and TAGs are either stored or used for energy
- left with LDL
- LDL is taken up by the liver via LDL-receptors
41
High-density lipoprotein (HDL)
- initially released from the liver "empty"
- cholesterol is extracted from plasma membranes and then esterified directly on HDL
- most blood cholesterol is esterified with a fatty acid
- reverse cholesterol transport: when HDL picks up cholesterol around the body and brings it to the liver
42
Reverse cholesterol transport enzymes
LCAT: esterifies a fatty acid to cholesterol
SR-B1: transports cholesterol from HDL into the liver
CETP: transfers cholesterol from HDL to VLDL and/or LDL
*CETP and SR-B1 are 2 different fates
43
what can happen to cholesterol in the liver?
1. converted into bile acids to replenish the bile acid pool (good - reduces blood cholesterol levels)
2. secreted "as is" directly with bile, to be eliminated in feces
3. packaged into VLDL and sent around the body
44
Summary of lipid transport and cholesterol circulation
1. chylomicrons are assembled in the intestine and enter the lymphatic system, deliver TAGs to tissues and become chylomicron remnants
2. De Novo cholesterol ester and TAG synthesis happens
3. VLDL circulates to peripheral tissues, TAGs are hydrolyzed - and become IDL which are either taken up by hepatic LDL-R or further hydrolyzed into LDL
4. reverse cholesterol transport - HDL carries cholesterol to liver or CETP mediates the transfer of CEs to LDL
5. cholesterol is eliminated from the body by conversion to bile acids or secreted as is
45
main takeaways from LDL and HDL
- LDL delivers cholesterol for essential functions BUT can also deposit cholesterol in unwanted places (too much creates risk for cardiovascular disease)
- higher HDL levels means more cholesterol returning to the liver
46
Lipid metabolism in the liver following a meal
hepatocyte cell
- chylomicron remnants in the portal vein release components (TAGs are broken up from before)
- FFA contributes to FA pool, MG and DG contribute to the TAG pool, phospholipids and cholesterol go straight to Apos
- all components are transferred into VLDL or HDL and enter systemic circulation
47
lipid metabolism in adipose tissue following a meal
adipocyte cell
- TAGs are released from lipoproteins in blood vessels and enter the cell
- some become FFAs and contribute to the fatty acid pool
- extra glucose supports the synthesis of fat in adipose tissue
- adiposites accumulate triglycerides and store them
48
What metabolic pathways do lipids fit into?
Gluconeogenesis: the glycerol backbone in glucogenic
Kreb's cycle: fat oxidation via acetyl CoA
49
Lipolysis and gluconeogenesis (TAGS)
- lipases hydrolyze ester linkages (lipolysis) - break TAGS to access fatty acids
- in adipose tissue, HSL cleaves a fatty acid from the glycerol backbone (can be inhibited by insulin)
- the complete breakdown of a TAG molecule releases one glycerol and 3 fatty acids
- glycerol can enter into glycolysis or gluconeogenesis
- fatty acids can undergo B-oxidation and be used to generate ATP
50
B-oxidation and Kreb's cycle
Steps in B-oxidation: dehydrogenation, hydration, oxidation, thiolysis
- each round of B-oxidation removes 2 carbons ( produces an Acetyl CoA) and produces 1NADH and 1 FADH2
e.g. a 16 carbon FA will produce 8 acetyl CoA and 7 NADH and FADH2
- FADH2 and NADH go onto the ETC
- Acetyl CoA goes onto the Kreb's cycle
51
recommended caloric intake of macronutrients
based on a male 2500kcal/day diet
- protein is 10-35% (218g/day max)
- CHO is 45-65% (406g/day max)
- fat is 20-35% (97g/day max)
52
effects of dietary cholesterol
- for healthy people, dietary cholesterol doesn;t change blood cholesterol much
- for unhealthy people (with high blood cholesterol), decreasing dietary cholesterol will decrease LDL
53
Trans fatty acids
- unsaturated FAs with at least one double bond in the trans-configuration
- both industrial and natural
Natural: no negative health consequences
Industrial: produced during the hydrogenation of vegetable oils (VERY BAD)
54
Why and how do companies create trans fats?
- to increase stability during cooking
- longer shelf life
- palatability
- hydrogen atoms are added catalytically across double bonds
- partial hydration: converts cis to trans
- complete hydration: results in all double bonds becoming fully saturated
- banned in Canada as of 2018
55
Trans fats found naturally in ruminant fat
- milk fat contains 4-8% trans fat (CLA)
- made in the rumen through bacterial fermentation
-
56
CVD risk with trans fats
high intake of industrial trans fats can lead to...
- high LDL cholesterol
- high total cholesterol
- increased inflammation
- lowered HDL cholesterol
on a per calorie basis, trans fats appear to increase the risk of CVDmore than any other nutriend
