Lipids Flashcards
characteristics of lipids
- 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
lipid functions (8)
- 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)
saturated fatty acids
- maximum number of hydrogens
- only single bonds
- butyric acid: in the stomach - from bacteria
- palmitic acid: most common that we eat
monounsaturated fatty acid
- missing hydrogens
- only one double bond
- oleic acid: 18:1 cis-configuration
- elaidic acid: 18:1 trans-configuration
polyunsaturated fatty acid
- missing hydrogens
- multiple double bonds
- the more double bonds, the more kinked the structure, the more fluid the membrane
omega system nomenclature
- 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
delta system nomenclature
- 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
essential fatty acid discovery
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
what are the essential fatty acids?
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
signs of omega-6 deficiency
skin: dermatitis (water leaves the membrane, leads to lost moisture and potential infection)
growth: decreases
reproductive maturity: decreases
CNS and retinal development are OK
signs of omega-3 deficiency
skin, growth and reproduction are OK
CNS development: IQ decreases
Retinal development: visual acuity decreases
who is most susceptible to EFA deficiency
infants: formula isn’t properly designed
hospitalized patients: fluid diets don’t contain proper amounts of EFAs
how much EFAs in our diet do we need to avoid deficiency?
omega-6 = 2-3% of energy in diet
omega-3 = 1% of energy in diet
why can an imbalance of omega3 and 6 cause problems
n-6 is used to make pro-inflammatory molecules
n-3 is used to make anti-inflammatory molecules
what makes pets susceptible to EFA deficiency?
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
EFA desaturation and elongation
- converts ALA and LA to downstream metabolites (humans are not good at this)
- desaturation removes hydrogen (creates DB)
- elongation adds 2 carbons
how does linoleic acid (18:2 n-6) lead to pro-inflammatory eicosanoid production?
- linoleic acid -> gamma-linoleic acid (via delta-6 desaturase)
- -> dihomo-gamma-linoleic acid (via elongase 5)
- -> arachidonic acid (via delta-5 desaturase)
how does alpha-linoleic acid (18:3 n-3) lead to anti-inflammatory eicosanoid production?
- 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
linoleic acid metabolism
- 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
what are eicosanoids?
- 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
how do we produce eicosanoids?
- 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
What are triglycerides (TAGs)?
- 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
what are phospholipids?
- 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
what are Sterols?
- 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
lipid digestion: mouth
lingual lipase is continuously secreted and starts to digest TAGs
lipid digestion: stomach
- gastric lipase is continuously secreted and targets TAGs
- lipase is stable at low pH (stomach acid)
lipid digestion: liver and gallblader
- liver makes bile acids (salts)
- gallbladder stores bile salts
- gallbladder releases bile, triggered by hormones
lipid digestion: small intestine
- pancreatic enzymes include pancreatic lipase, cholesterol and esterase to digest lipids
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
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
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
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
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)
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”
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
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
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”
Chylomicron Remnants
- TAG depleted chylomicrons
- removed from the circulation through ApoE-mediated interactions with a receptor in the liver
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
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
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
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
what can happen to cholesterol in the liver?
- converted into bile acids to replenish the bile acid pool (good - reduces blood cholesterol levels)
- secreted “as is” directly with bile, to be eliminated in feces
- packaged into VLDL and sent around the body
Summary of lipid transport and cholesterol circulation
- chylomicrons are assembled in the intestine and enter the lymphatic system, deliver TAGs to tissues and become chylomicron remnants
- De Novo cholesterol ester and TAG synthesis happens
- 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
- reverse cholesterol transport - HDL carries cholesterol to liver or CETP mediates the transfer of CEs to LDL
- cholesterol is eliminated from the body by conversion to bile acids or secreted as is
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
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
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
What metabolic pathways do lipids fit into?
Gluconeogenesis: the glycerol backbone in glucogenic
Kreb’s cycle: fat oxidation via acetyl CoA
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
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
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)
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
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)
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
Trans fats found naturally in ruminant fat
- milk fat contains 4-8% trans fat (CLA)
- ## made in the rumen through bacterial fermentation
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
