Section 4: Lipids

What are the functions of lipids

1. Storage of energy for the body (as adipose tissue)

2. Structural function

   • Cell membrane

   • Brain structure lipids

3. Signalling

   • Hormone function

   • Mediators of ETC

   • Gene expression

   • Pro/anti inflammatory mediators

4. Fat-soluble vitamins (A, D, E, K)

Describe the properties of lipids

1. Lipophilic

   • Soluble in organic solvents

   • Work well with other lipids

2. Hydrophobic 

   • Insoluble in water

   • Minimize contact with water

List the classes of lipids

1. Simple lipids

   • Fatty Acids

   • Tri-, di-, monoacylglycerols

2. Compound Lipids

   • Phospholipids

   • Glycolipids

3. Derived Lipids

   • Sterols, steroids

Describe the characteristics of fatty acids and how they affect the physical property of fats

1. Simplest of all lipids

2. Source of energy:

   • most calories of dietary fat come from fatty acids

3. Chain length

   • Long-chain fatty acids: 14-24 carbons (>12 carbons)

   • Medium chain: 6-12 carbons (human milk, dairy)

   • Short-chain fatty acids: 2, 3, 4 carbons (bacteria)

• Natural fats are usually have an even number of carbons

• Most of the edible oils are 16 or 18 carbons

What are the 3 types of FAs

1. Saturated Fatty Acids (SFA):

   • No double bonds, all carbons have 4 bonds

2. Monounsaturated Fatty Acids (MUFA):

   • One double bond

3. Polyunsaturated Fatty Acids (PUFA):

   • Multiple double bonds (2-6)

   • Increased bends and conformational change

Explain melting point in FAs

Higher melting point (bonds are stronger)

• longer chain (more bonds)

• not many double bonds (more linear, more stable)

Lower melting point (bonds are weaker)

• smaller chain (less bonds)

• many double bonds (more kinks, less stable)

Explain the differences in of double bonds in FAs

cis double bonds

• unsaturated fast

• arms in the same direction

trans double bonds

• most trans fats are from industrial processing

• some are from bacterial hydrogenation of PUFA by ruminants

  • not as bad since it’s from natural sources

• arms in opposite direction

Explain FA nomenclature for biochemists and nutritionists

#C : where double bond Δ

• from the carboxylic end

#C : where double bond

• from the methyl end

• omega 3 fats or omega 6 fats

Give examples of dietary sources for the individual fatty acids

• Saturated Fatty Acids (SFA):

  • Coconut oil

  • Animal and plant fats

  • peanuts

• Monounsaturated Fatty Acids (MUFA):

  • Plants, nuts, marine

  • Olive oil

• Polyunsaturated Fatty Acids (PUFA):

  • Corn, sunflower, peanut oil

  • Linseed, soybean oil

  • Fish oil

Which FA is an essential FA and which type of FA is it?

linoleic acid + α-linoleic acid

these are unsaturated FAs (has double bonds)

needs these fats to make longer chain PUFAs

Omega-3 FAs (ALA, EPA, DHA) have been associated with what?

improved cardiovascular, metabolic, and cognitive health in childhood and adulthood but no consistent evidence across populations

Explain neutral FAs

simple lipids → Mono-, di-, triacylglycerols

• one, two, three FAs esterified to glycerol

• can be a combination of saturated and unsaturated FAs in a chain

• make up 95% of dietary fats

Explain the sn positions

glycerol + 3 FAs = triacylglycerol

• attached by an ester bond

sn-1 is the first carbon position (top)

sn-2 middle carbon

sn-3 on the third carbon (bottom)

Draw the path of the components of membrane lipids

Explain the biological role of phospholipids

1. Structural support in cell and organelle membranes

   • Phospholipids have two fatty acids (hydrophobic tail) and a hydrophilic end

   • Help with fluidity

2. Physiologically active compounds

   • e.g., release of arachidonate from phosphatidylcholine and phosphatidylinositol for formation of eicosanoids

3. Participation in immune function:

   • phosphatidylinositol anchors surface antigens

4. Second messenger in cell signalling

   • hormonal (insulin) stimulation; messenger triggers activation of enzymes and hormonal responses

What are the different types of phospholipids that are major components of mammalian cell membranes

glycero-phospholipid structure

• glycerol + phosphate + 2 FAs + compound

  • Choline - phosphatidylcholine (most common)

  • Ethanolamine - phospatidyl-ethanolamine 

  • Serine - phosphatidylserine

  • Inositol - phosphatidylinositol

Explain sphingolipids made from phospholipids and glycolipids

phospholipid:

sphingomyelin structure

• sphingosine + phosphate + FA + compound

  • choline

  • ethanolamine

glycolipid:

cerebroside = sphingosine + FA + GLU/GALAC

ganglioside = sphingosine + FA + oligo. + sialic acid

What is the role of sphingomyelin?

myelin sheaths in the nervous system

What is the role of cerebroside and ganglioside?

structural role in medullary sheathes of nerves and brain tissue

Where do sterols occur?

only in animal

• meats, egg yolk, dairy products

• sterols + phospholipids = 5% of dietary fat

• sterols are versatile → precursor for bile acids, steroid hormones, and vitamin D

Which organs digest fats?

• mouth

• stomach

• small intestine

Explain fat digestion in the mouth

• teeth use mechanical separation of nutrients to increase SA

• serous glands release lingual lipase (gets activated in the stomach)

Explain fat digestion in the stomach

• Most digestion is in the stomach

• Activate lingual lipase released from the mouth

• Release gastric lipase (chief cells)

• both enzymes are stable in low pH

• they digest TAGs (prefer SCFA and MCFA) and prefer the cleave the FA at the sn-3 position

• digest 10-30% of TAGs

• secretion of both lipases occur continuously but can be stimulated by

  • neural factors (sympathetic nervous system)

  • dietary factors (high fat)

  • mechanical (sucking/swallowing)

  
  

• fats are emulsified to increase SA

• undigested lipids delay gastric emptying → high satiety

• enterogastrone released by duodenal mucosa may reduce gastric motility

• mix bolus by smooth muscles

• shear forces by pyloric sphincter

Explain fat digestion in the stomach for infants

• pancreatic function is not fully developed

• gastric and lingual lipases enter fat globules without emulsifiers

• short and medium CFA are in the sn-3 position for better digestion for the infant

Explain fat digestion in the small intestine

• more emulsification by shear forces

• release CCK from intestinal cells

  • stimulate pancreas + gallbladder to..

    • secrete bile acids, pancreatic enzymes, bicarbonate

What is fat emulsification?

• bile acids form an exterior surface covering lipid droplets

• prevents lipids from grouping together

What is bile acid and where is it made?

• amphipathic molecules made from cholesterol in the liver

cholic acid / chenodeoxycholic acid = bile acid

• 75% → glycocholic acid / glycochenodeozycholic acid = conjugated bile acid + glycine

• 25% → taurocholic acid / taurochenodeoxycholic acid = conjugated bile acid + taurine

conjugation with glycine or taurine for…

• better ionization

• improved ability to form micelles

What’s the difference between bile acid and bile salts?

bile acid:

• original steroid compound

• produced by the liver from cholesterol

bile salts:

• active, water-soluble

• bile acid + amino acid

• used to make micelles in fat digestion

Explain emulsification of bile acids

fat droplet is attached to the conjugated bile acid on the hydrophobic end while the hydrophilic side of the conjugated bile acid is facing outwards

Name examples of emulsifiers

• complex polysaccharides

• phospholipids

What are the pancreatic enzymes secreted in fat digestion

1. pancreatic lipase

   • Need colipase and calcium ions and bile salts to work

   • Hydrolyzes sn-1 first then sn-3 bonds

   • If gastric/lingual lipase already took the sn-1 bond, then pancreatic lipase will take off sn-3

2. cholesterol esterase

   • Hydrolysis of cholesterol esters → cholesterol + FA

3. phospholipase A₂

   • Hydrolysis of sn-2 FA from lecithin → lysolecithin + FA

At the end of fat digestion, what are you left with?

mixed micelles (5 nm diameter) ready for absorption

• monoacylglycerols

• free FAs

• free cholesterol

• cholesterol esters

• lysophospholipids

• fat-soluble vitamins

• bile salts (stabilize micelles)

Explain fat absorption

1. FAs < 12 C are bound to albumin → portal vein

1. Longer FAs, MAGs, LPL (lysophospholipid) move to the endoplasmic reticulum

2. At the ER, Acyl-CoA synthetase binds FAs and coenzyme-A (uses one ATP) and now they are ready for binding facilitated by FATP

3. FA-CoA molecules are re-esterified by

   • acyltransferase

     • MG + 2 FA-CoA = TAG

     • LPL + 1 FA-CoA = PL

   • acyl-coA:cholesterol acyltransferase 2 (ACAT2)

     • C + 1 FA-CoA = cholesteryl ester

How much of TAG and cholesterols consumed are absorbed?

95% TAG

40-50% cholesterol

How do lipids get into circulation when it is hydrophobic? Via what

lipid transport from…

• intestine to different tissues (in fed state)

• endogenous formation/storage to different tissues

What is a chylomicron and explain its structure

• in intestinal cells, esterified lipids are packed for transport into chylomicrons

exterior (hydrophilic): phospholipids + cholesterol + apolipoproteins

interior (hydrophobic): TAGs, cholesterol esters

• tags are the most abundant in the diet so it’s the most abundant in chylomicrons

What is the function of chylomicrons?

to deliver dietary lipids to muscle and adipose tissue

• the liver should not be taking the chylomicrons

Explain the pathway of chylomicrons when they leave the intestinal cell

chylomicrons leave intestinal cell via exocytosis → lacteal → lymphatic circulation → blood circulation

When is the peak level of lipid plasma? How long does it take to rebalance?

peak level: 0.5 - 3 hours in fed state

rebalance in 5-6 hours

• can recirculate for 14 hours

How are chylomicrons delivering fats to tissues that’s not the liver?

chylomicrons stay in the blood vessels (intravasular hydrolysis)

1. chylomicrons are catalyzed by lipoprotein lipase which is activated by apoC-2 on the chylomicron surface

2. LPL cleaves TAGs → MAGs + 2 FAs to enter cell

• over time circulation of lipoprotein lipase diminish chylomicrons of TAGs

• chylomicron remnants is what is left over and accepted by the liver (left over 20% fats)

Explain the role of insulin and glucagon in terms of lipoprotein lipase

insulin increase lipoprotein lipases in skeletal muscle and adipose tissue to encourage fat uptake

glucagon increase lipoprotein lipase in muscle without affecting adipose tissue

What happens after the chylomicron remnant is sent to the liver?

lipids are consumed or repacked as very low density lipoprotein and sent into circulation

What does VLDL contain?

1. endogenous lipids

2. free FAs from the adipose tissue

3. shorter FAs from the portal vein

4. TAG formation in ER

Explain the function of VLDL

• transport and delivery of endogenous lipids to peripheral tissues via lipoprotein lipase

Explain the differences of chylomicrons and VLDLs

chylomicron:

• ApoC 1-3, E

• ApoB-48

• Transport to muscle and adipose tissue

• Lipids used for oxidation and storage

• Energy storage for muscle

VLDL:

• ApoB-100

• ApoC 1-3, E

• Transport to adipose tissue

• Lipids used to form TAGs

• Leftover lipids are stored in adipose tissue

When lipids get absorbed, the size and composition of lipoproteins change. What do the Apo proteins do in response?

Apo proteins change based on the current state and purpose

What is the function of apolipoproteins (apo)?

• to stabilize lipoproteins in aqueous environment

• to be recognized by specific receptors

• stimulate certain enzymatic reactions

What i s

Explain what a low density lipoprotein is and its function

function: cholesterol transport

• IDL reduced to LDL

• cholesterol makes up 50%

  • cholesterol is taken up by cells from LDL by a receptor mediated process

  • cellular receptors recognize apoB-100 on LDL

    • 1. LDL contacts with receptor

    • 2. enter cell and connect with lysosome

      • LDL uptake inhibits HMG CoA reductase

      • LDL uptake receptor synthesis

    • 3. cholesterol is used or transported to golgi aparatus for storage

      • ACAT converts cholesterol to cholesterol esters

Explain what a high density lipoprotein is and its function

function: reverse cholesterol transport (good cholesterol)

• collect excess cholesterol → transport to liver → used or eliminated

• carries 20% of plasma cholesterol, has a lot of phospholipid

• apoA1 is the major lipoprotein in HDL

  • activates lecithin cholesterol acyltransferase (LCAT) which forms cholesterol esters

• CE migrate ot the core of HDL

• transport to liver

• use/excretion of cholesterol via bile acid formation in the liver

Explain why LDL is bad

• LDL transports cholesterol to cells

• if LDL is not taken up by the cells, it keeps circulating in the blood

• the longer LDL circulates in the blood, the more likely it’ll oxidize

  • uptake by macrophage

  • foam cell formation

  • fatty plaques

  • artheroclerosis

Explain the steps of development of atherosclerosis

• oxidized LDL in blood vessels

• taken up by macrophages

• monocytes phagocytose LDL creating foam cells

• fatty plaques form

• narrowing blood vessels

How can you test lipid profile?

• blood test at fasting state

• measure plasma or serum

• look for total cholesterol: LDL cholesterol, HDL cholesterol, TAGs

• healthy adults ≥ 40 test every 5 years

• higher risk test once a year

Explain the personal causes of dyslipidemia

1. genetic predisposition

   • reduced expression or binding capacity of LDL-receptors

   • reduced cholesterol uptake

2. lifestyle factors/chronic disease

   • intake > expenditure

   • stress

   • overweight/obesity

   • insulin resistance

   • diabetes

What is the desired ration of LDL:HDL to reduce risk of artherosclerosis

↓ LDL: ↑ HDL

overall ↓ ratio is better

What are the diet causes of dyslipidemia?

1. Quality of dietary fat / composition of fatty acids

2. Dietary cholesterol (in some cases): role of plant sterols

3. Fiber intake

4. Source of protein (animal versus plant protein)

5. Coffee consumption

6. Lifestyle factors including exercise (another course)

Explain alternatives in SFAs. Explain good sources that don’t increase LDL

lower LDL → lower palmitic acid sources for carbs or stearic acid

SFA in dairy don’t increase LDL

Cheese intake lowers LDL compared to butter intake of equal fat content H

Explain how FA composition impact clearance of LDL

• impacts apoB100 interaction with receptors

• more SFAs in LDL makes a stiffer LDL which is less moudable

• less apoB100 and LDL-receptor interactions

• LDL doesn’t interact with receptors and continues to circulate in the blood

List and explain other sources of better quality fats

monounsaturated fatty acids (MUFAs): nuts, dairy, olive oil

• lower LDL, increase HDL

polyunsaturated fatty acids (PUFAs)

• reduce TAGs

• reduce blood clotting

• reduce release of inflamatory cytokines involved in plaque formation

• omega 6 FA

• omega 3 FA

Explain another quality of fat that isn’t good

Trans fatty acids

• have greater hypercholesterolemic effect compared to SFAs

• increase [LDL]

• no change in [HDL]

Explain how dietary cholesterol cause dyslipidemia

• may or may not impact plasma cholesterol levels

• depends on

  • chronic intake of low dietary cholesterol

  • responder or not

    • 70% people can adjust changes in dietary cholesterol levels

    • 20-30% are hyper-responsive to dietary cholesterol

      • they can’t regulated endogenous cholesterol so their plasma cholesterol level changes

Explain how fibre intake cause dyslipidemia

• fiber intake lead to redcued plasma cholesterol

1. insoluble fibers speed up movements in GI + soluble fibers reduce mixing of chyme with digestive enzymes (gels - ‘physical barrier’).

   • Both effects lead to increase bile/cholesterol excretion;

2. Bile composition changes

   • liver gets LDL from blood for new bile production, which inhibits HMG CoA reductase enzyme required for cholesterol synthesis

3. Production of short chain fatty acids by colonic fermentation of soluble fibers → inhibits cholesterol + fatty acid synthesis

4. Replacement of high-fat foods

Explain how protein sources cause dyslipidemia

animal derived protein has hypercholesterolemic effect

• higher SFA content

plant derived protein has hypocholesterolemic effect

• plant sterols are rich in fiber

• but engineered meat may not be as healthy

Explain how coffee consumption cause dyslipidemia

• brewed coffee has cafestol which is a stimulator of LDL

• there are different cafestol levels in different prepared coffees

• unfiltered and pressed coffee have high levels of cafestol

Explain how humans can endogenously make SFAs and MUFAs

• acetyl-CoA is used to make FAs

• can elongate to become long carbon SFAs

• SFAs can become desaturated and become MUFAs

What is the ideal omega-6:omega-3 FA ration?

1:1

but our diet has more omega-6 than 3s

Why do we need omega-6 FAs?

converstion of ALA to EPA and DHA (Omega3) depend on omega-6 FA

What are the benefits of omega6 and omega3 PUFAs?

• anti-inflammatory…

  • prostaglandins

  • leukotrienes

  • resolvins

Explain the pathway of lipid (with glucose) absorption in the liver

glucose-6-p can go through….

• replenish glycogen stores

• α-glycerol-3-phosphate → form DAGs and TAGs

• HMP shunt → NADPH for FA synthesis

• form acetyl-CoA to form malonyl CoA for endogenous synthesis of FAs

Explain the fates of cholesterol and cholesterol esters from chylomicron remnants that are taken up by the liver

• convert to bile salts and secret in the bile

• be incorporated into VLDL and released into blood

Explain the fates of FAs in the liver

• go into TAG pool

• be incorporated into VLDL and released into blood

Explain the role of insulin in lipid metabolism

• insulin stimulates lipoprotein lipase in adipocytes

  • LPL hydrolyzes TAGs in chylomicrons and VLDL

  • free FAs are taken up in adipocytes → re-esterified to TAGs for storage

• insulin inhibits hormone-sensitive lipase in adipocytes preventing hydrolysis of stored TAGs going into the FA pool

  • remove lipids in blood, store in adipose tissue

Explain the pathway of lipid (with glucose) absorption in adipose

glucose-6-p can go through….

• α-glycerol-3-phosphate → form DAGs and TAGs

• HMP shunt → NADPH for FA synthesis

• form acetyl-CoA to form malonyl CoA for endogenous synthesis of FAs

Explain the fates of FAs and lipids in the adipose

FAs: FA pool

lipids: into storage

How much of an adipocyte is fat?

85% of adipocyte is fat

Explain what happens in the post-absorptive and fasting state in the adipose tissue

1. glucagon and epinephrin are released

2. activate hormone-sensitive lipase

3. hydrolyze TAGs → FAs + glycerol

4. release FAs bound to albumin into blood

5. release glycerol to the blood for gluconeogenesis in the liver

Explains what happens in the post-absorptive state in the liver

hungry so you need energy…

TAG formation

• free FAs released from adipose tissue + bound to albumin

• they get taken up by peripheral tissues

• form TAGs in the liver

• incorporate TAGs into VLDL in the liver

FA oxidation in the mitochondria (energy for liver)

• form acetyl-CoA via β-oxidation

• acetyl-coA enter TCA cycle

• ATP synthesis

Excess acetyl-CoA / ketogenesis

• acetyl-Coa → acetoacetate → β-hydroxybutyrate and Acetone

• ketone bodies are energy precursors for the liver