Ch. 10 Summary Notes: Lipids

Lipids Overview

• Often referred to as fats, but fats are just lipids that are solid at room temperature.
• Oils are lipids that are liquid at room temperature.
• Lipids are insoluble in water and have many diverse functions, including:
  • Energy storage.
  • Structural components of membranes.
  • Cell signaling compounds.
• Lipids are nonpolar.

Lipid Classes

• Lipid Classes:
  • Free Fatty Acids: Essential FA
  • Triacylglycerols: Long-term E storage
  • Phospholipids: Mostly
  • Glycolipids:
  • Steroids: Cholesterol, Steroid hormones
• Functions:
  • Storage lipids: E stored in hydrocarbon
  • Membrane lipids
  • Lipid signals

Fatty Acids: Storage Lipids

• Derived from highly reduced hydrocarbon compounds called fatty acids.
• Called 'acids' because one end contains a carboxylic acid.
• Most are even numbered.
• Range in number of carbons from 4 to 36; most common lengths are 12-24 carbons.
• Range in number of double bonds:
  • 0 double bonds = saturated fat (SFA).
  • 1 double bond = monounsaturated fatty acid (MUFA).
  • 2+ double bonds = polyunsaturated fatty acid (PUFA).
• Energy:
  • Lipids provide $9$ kcal/g.
  • Found in reduced form = lots of H!!
  • One pound of fat contains $3,500$ kcal.
  • To lose 1 pound/week, create a 500 kcal deficit per day.
  • To gain 1 pound/week, eat 500 kcal/day more than energy expenditure.

Fatty Acids: Hydrophilic and Hydrophobic Properties

• Hydrophobic: Tail with hydrocarbon chain.
• Hydrophilic: Head with carboxylic acid, ionized at physiologic pH (also called acyls).

Fatty Acids: Classification

• Fatty Acid (FA) Classification
  • Number of carbons (chain length)
    • Short chain: 4-6 C long, butyric acid
    • Medium chain: 8-12 C long, lauric acid
    • Long chain: 14-24 C long, palmitic acid, essential fatty acids
  • Number of double bonds (saturation)
    • Saturated (SFA): No double bonds, fats
    • Monounsaturated (MUFA): 1 double bond, oils
    • Polyunsaturated (PUFA): >1 double bond, oils

Fatty Acids: Saturation

• Saturated fatty acid (SFA):
  • No double bonds.
  • Fats at room temperature.
• Monounsaturated fatty acid (MUFA):
  • 1 double bond.
  • Generally oils at room temperature.
• Polyunsaturated fatty acid (PUFA):
  • Greater than 1 double bond.
  • Oils at room temperature.
• Double bonds have methylene ($CH_2$) group in between = methylene interrupted, allowing a more flexible structure. Addition of 1 or more double bonds adds a kink into the structure; does not allow it to pack tightly, it is more likely to form an oil.

FA Nomenclature

• Two ways of numbering double bonds: delta ($\Delta$) and omega ($\omega$).

Delta (Δ) Nomenclature

1. Chain length (number of carbons)
2. Colon
3. List the number of double bonds
4. Count from delta end (carboxyl end)
5. List first C in ALL double bonds
   • Ex. 18:1$\Delta$9

Omega (ω) Nomenclature

1. Chain length (number of carbons)
2. Colon
3. List the number of double bonds
4. Count from omega end
5. List first C in FIRST double bonds
   • Ex. 18:1$\omega$9 (often n replaces $\omega$)
   • Double bonds continue every 3.

FA Nomenclature: Delta and Omega Numbering

• Delta numbering: List all the numbers of $\Delta$
• Omega numbering: Only put one number with $\omega$
• No Double Bonds
  • 18:0 Saturated
  • 18:0 fats
• Double bonds are always 3 C apart!!
  • $\Delta$ 18:2 $\Delta$9,12
  • $\omega$ 18:2 $\omega$6

Shortcut From delta to omega

1. Subtract the LAST bond number from the total C in chain.
   • Ex. 18:2$\Delta$9,12
     • 18-12 = 6
     • 18:2$\omega$6

From omega to delta

1. Subtract the bond number from the total C in chain. This represents the LAST delta bond.
2. If there are more bonds, subtract 3 to get each additional bond.
   • Ex. 18:2$\omega$6
     • 18-6 = 12
     • 12-3 = 9
     • 18:2$\Delta$9,12

Common Patterns in Fatty Acids (FA)

• Even number of carbons
• Most common contain 12-24 carbons
• Most common bond is between C9 & C10 (delta end)
• Double bonds are 3 carbons apart

Short & Medium Chain Saturated Fatty Acids

• 3:0 Propionic acid, propanoic acid, fermented foods
• 4:0 Butyric acid, butanoic, butter, goat milk
• 6:0 Caproic acid, hexanoic, goat milk
• 8:0 Caprylic, octanoic, goat milk
• 10:0 Capric, decanoic, goat milk
• 12:0 Lauric acid, dodecanoic, coconut oil

Long Chain Saturated Fatty Acids

• 14:0 Myristic acid, tetradecanoic, coconut oil, palm oil
• 16:0 Palmitic acid, hexadecanoic, palm oil, cocoa butter
• 18:0 Stearic acid, octadecanoic, animal fats, cocoa butter
• 20:0 Arachidic acid, eicosanoic acid, peanut oil, corn oil, cocoa butter
• 24:0 Lignoceric acid, tetracosanoic acid, peanut oil

Monounsaturated Fatty Acids (MUFA)

• 16:1$\Delta$9, 16:1$\omega$7, Palmitoleic acid, Cis-9-hexadecenoic acid, Fish oil, macadamia nuts
• 18:1$\Delta$9, 18:1$\omega$9, Oleic acid, Cis-9-octadecenoic acid, Olive oil, canola oil
• 24:1$\Delta$15, 24:1$\omega$9, Nervonic acid, Cis-15-tetracosenoic acid, Seed oils, like flax

Polyunsaturated Fatty Acids (PUFA)

• 18:2$\Delta$9,12, 18:2$\omega$6, Linoleic acid, Cis,cis-9,12-octadecadienoic acid, Corn, soy & sunflower oils
• 18:3$\Delta$9,12,15, 18:3$\omega$3, α-linolenic acid (ALA), Cis,cis,cis-9,12,15-octadecatrienoic acid, Flax, pumpkin, kiwi seeds, canola oil
• 20:4$\Delta$5,8,11,14, 20:4$\omega$6, Arachidonic acid (ARA), Cis,cis,cis,cis-5,8,11,14-icosatetraenoic acid, Animal fats, eggs
• 20:5$\Delta$5,8,11,14,17, 20:5$\omega$3, Eicosapentaenoic acid (EPA), Cis,cis,cis,cis,cis-5,8,11,14,17-icosapentaenoic acid, Fish, algae, omega-3 eggs
• 22:6$\Delta$4,7,10,13,16,19, 22:6$\omega$3, Docosahexaenoic acid (DHA), Cis,cis,cis,cis,cis,cis-4,7,10,13,16,19-docosahexaenoic acid, Fish, algae, breast milk, omega-3 eggs

FA in Foods

• Most natural fats in foods vary in composition of fatty acids
  • Olive oil: High in C16 & C18 Unsat.
  • Butter: High in C4-C14 Sat.
  • Beef: High in C16 & C18 Sat.

Essential Fatty Acids

• Humans cannot synthesize omega-3 and omega-6 fatty acids because we lack the enzymes called desaturases (add double bonds) specific for n-1 to n-7 end
• Most common essential fatty acids we consume are the 18C variety:
  • Linoleic acid (18:2n-6)
  • Alpha-linolenic acid (ALA; 18:3n-3)

Omega-6 Fatty Acids

• Linoleic acid (18:2$\Delta$9,12)
• γ-linolenic acid (18:3$\Delta$6,9,12)
• Eicosatrienoic acid (20:3$\Delta$8,11,14)
• Arachidonic acid (20:4$\Delta$5,8,11,14)
• Functions:
  1. Prevent water loss from skin
  2. Cell signaling
  3. Blood clotting

Omega-3 Fatty Acids

• α-Linolenic acid (18:3$\Delta$9,12,15)
• Eicosapentanoic acid (20:5) [EPA]
• Docosahexaenoic acid (22:6) [DHA]
• Functions:
  1. Thins blood
  2. Anti-inflammatory
  • Functions:
    1. Cell signaling
    2. Important component of phospholipids in brain & retina

Fatty Acid Conversion

• Linoleic acid 18:2n-6 - γ-Linolenic acid 18:3n-6 - Dihomo-γ-Linolenic acid (DGLA) 20:3n-6 - Arachidonic acid (AA) 20:4n-6 - Docosapentaenoic acid 22:5n-6
• Alpha Linolenic acid (ALA) 18:3n-3 - Eicosapentaenoic acid (EPA) 20:5n-3 - Docosahexaenoic acid (DHA) 22:6n-3
• Enzymes: $\Delta$6 Desaturase, $\Delta$5 Desaturase, $\Delta$4 Desaturase
• cofactors: Mg, B6, Zn, Vit. A, C, niacin

Side Note: Grass-Fed vs Grain-Fed Beef

• Fatty acids:
  • Linoleic acid (18:2n-6):
    • Grass-Fed (mg/3 oz. serving): 104
    • Grain-Fed (mg/3 oz. serving): 132
  • Linolenic acid (18:3n-3):
    • Grass-Fed (mg/3 oz. serving): 45.7
    • Grain-Fed (mg/3 oz. serving): 5.3
  • EPA:
    • Grass-Fed (mg/3 oz. serving): 17.7
    • Grain-Fed (mg/3 oz. serving): 5.2
  • DHA:
    • Grass-Fed (mg/3 oz. serving): 1.7
    • Grain-Fed (mg/3 oz. serving): 1.2
  • Total MUFA:
    • Grass-Fed (mg/3 oz. serving): 205
    • Grain-Fed (mg/3 oz. serving): 388
  • Total n-6:
    • Grass-Fed (mg/3 oz. serving): 149
    • Grain-Fed (mg/3 oz. serving): 189
  • Total n-3:
    • Grass-Fed (mg/3 oz. serving): 86.4
    • Grain-Fed (mg/3 oz. serving): 21.8
  • Total SFA:
    • Grass-Fed (mg/3 oz. serving): 322
    • Grain-Fed (mg/3 oz. serving): 435

Side Note: Grass-Fed Beef vs. Salmon

• Total omega-3 (mg)/pound:
  • Grass-Fed Beef: 46.1
  • Salmon: 2724.8
• Price per pound:
  • Grass-Fed Beef: $4.50
  • Salmon: $8.00
• Omega-3 (mg)/$1:
  • Grass-Fed Beef: 10.0
  • Salmon: 340.6
• Protein (g/100g):
  • Grass-Fed Beef: 23.1
  • Salmon: 24.6
• Vitamin B12 (mcg/100g):
  • Grass-Fed Beef: 1.3
  • Salmon: 4.7
• Niacin (mg/100g):
  • Grass-Fed Beef: 6.7
  • Salmon: 9.6
• Zinc (mg/100g):
  • Grass-Fed Beef: 3.6
  • Salmon: 0.46
• Selenium (mcg/100g):
  • Grass-Fed Beef: 21.1
  • Salmon: 37.6

Properties of Lipids

• Longer carbon chain = less soluble in water
  • Short & medium-chain fatty acids are transported differently than long-chain after absorption
• More saturated (fewer double bonds) = more solid
  • Higher melting point in saturated fats (solid at room T)
  • MUFA & PUFA are oils

Smoke Point

• Highest temperature that oil can be used
• Temperature at which volatile compounds from oxidative damage begin to form soot
• Refined oils have many of the volatiles removed, so they have higher smoke points

Fatty Acid Composition & Smoke Point

• Coconut:
  • % MUFA: 6
  • % PUFA: 3
  • % SFA: 91
  • Smoke point (C): 175
  • Smoke point (F): 347
• Safflower:
  • % MUFA: 15
  • % PUFA: 75
  • % SFA: 8
  • Smoke point (C): 212
  • Smoke point (F): 414
• Canola:
  • % MUFA: 58
  • % PUFA: 32
  • % SFA: 10
  • Smoke point (C): 238
  • Smoke point (F): 460
• Extra Virgin Olive:
  • % MUFA: 72
  • % PUFA: 14
  • % SFA: 14
  • Smoke point (C): 195
  • Smoke point (F): 383

FA in Foods: Rancidity

• Lipids exposed to oxygen for too long become rancid and spoil
• Especially MUFA & PUFA, as oxygen like to attack double bonds
• Rancid aroma comes from oxidative breakage of double bonds that yield aldehydes & carboxylic acids with shorter carbon chains
• Shorter chains = more volatile = very smelly
• To improve shelf life and prevent spoilage, many commercial oils were converted to trans fats

Structural Isomerization of FA

• Cis – same side
  • Geometric isomers!!
  • Can still rotate
  • Most found in nature
• Trans – opposite side
  • Stuck in linear position
  • Few in nature, mostly synthetic

Trans Fat

• Behaves like a saturated fat in the body.

Hydrogenation

• $C=C + H_2 \xrightarrow{Nickel catalyst} C-C$
• Partially hydrogenated oil results in trans fat.
• Fully hydrogenated oil results in saturated fat (no trans).

Partially Hydrogenated Oils - Hidden Trans Fat

• Ingredients: PARTIALLY HYDROGENATED COTTONSEED OIL

Health Impact of Trans Fat

• All-cause Mortality: 1.34 (CI 1.16-1.56)
• Coronary Heart Disease (CHD): 1.42 (CI 1.05-1.92)

Meet Dr. Fred Kummerow

• Dr. Kummerow was a Professor Emeritus at University of IL
• He had been studying the effect of trans fat in the body since the 1940’s
• He petitioned the FDA in 2009 to ban trans fat
• Because nothing had been done, he sued the FDA in 2013 at the age of 99
• Passed away at the age of 102

Trans Fat Ban

• 2013 FDA preliminarily removed ‘generally recognized as safe’ (GRAS) status for partially hydrogenated oils (PHOs)
• 2015 FDA revoked GRAS status completely
• Food manufacturers will have 3 years (2018) to comply
• Out of the general food supply by June 2018 (with a few minor exceptions)

Free Fatty Acid Summary

• Separate based on chain length or saturation
• Essentials must be consumed
• Not often found free, usually bound in a larger structure called a TG

Long-term Energy Storage: Triacylglycerols

• AKA triglycerides
• Simplest lipid containing fatty acids
• Contain a glycerol backbone made of 3 carbons with 3 fatty acids attached
• Most natural triglycerides are mixed and contain multiple different fatty acids

Glycerol Backbone

• Stereospecific numbering (sn)
  • sn-1 $CH_2OH$
  • sn-2 $HO – CH$
  • sn-3 $CH_2OH$

Triglyceride (TG) Formation

• $CH<em>2 – OH + HO – C – R1 \rightarrow CH</em>2 – O – C – R1$
• $CH – OH + HO – C – R2 \rightarrow CH – O – C – R2$
• $CH<em>2 – OH + HO – C – R3 \rightarrow CH</em>2 – O – C – R3$
• + 3H2O
• What kind of reaction is this?
• What kind of bond is this?
• AKA Triacylglycerol (TAG)

Storage Lipids (Neutral)

• Can also refer to image

Triglycerides Provide Stored Energy

• Plants store lipids in germ of seeds
• TG are stored in lipid droplets in all cells
• Muscles contain intramuscular triglyceride pools essential for endurance exercise
• Adipocytes are special storage cells that store large amounts of TG

Triglycerides Provide Stored Energy: Advantages

1. Carbon atoms in fatty acids are more reduced than sugars, so oxidation of FA yields more than 2x as much energy per gram
   • Lipids provide 9 Cal/g, while carbs and proteins provide 4 Cal/g
2. Since TG are hydrophobic, fat storage doesn’t carry extra weight of water
   • Carbs carry 2x at much water per gram (2 g of water for every 1 g of carbohydrate)

• We store less than a day’s worth of energy as carbs – used for quick energy
• We store months of energy in adipocytes (~80,000 Cal worth)

White vs. Brown Adipocytes

• White:
  • Unilocular = 1 large lipid droplet
  • Less surface area
  • Energy storage
• Brown:
  • Multilocular = lots of smaller lipid droplets
  • More surface area
  • Energy thermogenesis
  • Formed from white adipocytes that have had appropriate stimuli

Structural Lipids

• Lipids used in membranes

Membrane Lipids (Amphipathic)

• Contain hydrophilic & hydrophobic regions
• Phospholipids
  • Glycerophospholipids
    • Ester phospholipids
    • Ether phospholipids
  • Sphingophospholipids
    • Sphingomyelin
• Glycolipids
  • Glycosphingolipids (carb)
    • Cerebrosides
    • Globosides
    • Gangliosides
• Sterols
  • Cholesterol

Phospholipids

• Glycerophospholipids:
  • Glycerol
  • Fatty acid
  • Fatty acid
  • $PO_4$
• Sphingophospholipids:
  • Sphingosine
  • Fatty acid
  • Polar head
  • $PO_4$
  • Choline

Glycerophospholipids

• Membrane lipids
• Made from parent compound called phosphatidic acid
• Named for polar head group:
  • Phosphatidyl choline
  • Phosphatidyl inositol

Glycerophospholipid

• $CH_2 – O – C$
• $CH – O – C$
• $CH_2 – O – P – O – X$
• O O O O-
• Polar head group varies for each phospholipid
• Usually saturated
• Usually unsaturated
• sn-1
• sn-2
• sn-3

Lipid Bilayer of the Plasma Membrane

• Polar head group on phospholipid
• Fatty acid tail on phospholipid
• Hydrophobic core

Phospholipid Functions

• Main component of membranes
• Stabilize proteins within the membrane
• Part of bile (aid in lipid absorption)
• Lipid transport (lipoproteins)
• Storage of signaling molecules (omegas, DG, IP3)

Glycerophospholipids Table

Phosphatidylserine & Apoptosis

• Phosphatidylserine is normally found on the inner leaflet of the plasma membrane, but moves to the outer leaflet during apoptosis signaling to WBC.

Cardiolipin (Diphosphatidylglycerol)

• Found exclusively in the inner mitochondrial membrane

Membrane Anchoring - Phosphatidylinositol

• Anchored protein = can be enzymes, receptors, etc.

Cell Membrane Signaling Steps

1. A hormone binds to a receptor starting a cascade of signals that activate phospholipase C.
2. Phospholipase C digests the inositol head group from phosphatidylinositol (PI) leaving a DG.
3. Inositol releases sequestered calcium from the ER. Ca + diglyceride activates protein kinase C (phosphorylating enzyme).

Ether Phospholipids

• Glycerol, Fatty acid, Fatty acid, $PO_4$, Polar head
• May have ether bond, rather than ester
• Main ether phospholipids in the body:
  • Plasmalogen
  • Platelet activating factor

Ether Glycerophospholipids Table

Plasmalogen

• Concentrated in brain (50%), heart, nerve & muscle

Platelet activating factor (PAF)

• Produced by platelets & white blood cells causing inflammation, hypersensitivity reactions, free radical formation & platelet aggregation

Membrane Lipids: Sphingolipids

• Sphingosine + Fatty acid = Ceramide
• Important in cell signaling & regulation of cell death
• Make up ~50% of lipids in stratum corneum (outermost layer of epidermis) – regulates water permeability of skin
• Too much can cause inflammation & cell death

Sphingolipids Overview

• Contain phosphate (phospholipid)
  • Sphingomyelin
• Glycolipids
  • Cerebrosides
  • Globosides
  • Gangliosides

Sphingolipids Types

• Sphingomyelin: Ceramide + P + choline
• Ganglioside: +3 or more branched sugars & N-acetylneuraminic acid
• Cerebrosides: +1 sugar
  • Usually glucose (non-neural tissue) or galactose (neural tissue)
• Globosides: +2-4 sugars
  • Usually glucose, galactose or N-acetylgalactosamine

Sphingophospholipid

• Sphingosine + Fatty acid + phosphate + choline = Sphingomyelin
• In plasma membranes of all animal cells
• Highly concentrated in myelin sheath of nerves

Sphingomyelin Location

Sphingolipids

• Often found on outer leaflet of plasma membrane
• Recognition sites
• Pattern of sugars gives specificity
• Greater than 60 different sphingolipids in the body

Phospholipid Degradation

• Occurs in the lysosome
• Each position requires a specific enzyme
• Genetic defects can lead to accumulation

Phospholipid Degradation Equations

• Enzyme, Product
• Phospholipase A1 (PLA1), Sn-1 fatty acid
• Phospholipase A2 (PLA2), Sn-2 fatty acid
• Phospholipase C (PLC), Polar head group + phosphate
• Phospholipase D (PLD), Polar head group only

Sphingomyelin Degradation

• Sphingomyelin $\xrightarrow{Sphingomyelinase}$ Ceramide = sphingosine + FA
• Niemann-Pick Genetic sphingomyelinase deficiency, resulting in Sphingomyelin accumulation causing mental retardation

Sphingomyelin Degradation Enzyme

Abnormal Accumulation of Glycolipids

Disease | Accumulation
Tay-Sachs disease | Ganglioside 3
Sandhoff disease |
Fabry disease |
Gaucher disease |
Krabbe |
Farber |
Niemann- Pick | Sphingomyelin

Symptoms | Blindness, muscle weakness, Neurodegeneration, CNS impairment, Joint deformity

Other Structural Lipid - Sterol

Cholesterol

• Steroid alcohol
• Made in animal tissues
• Synthesized in the liver, SI & specialized tissue
• Regulated by the liver

Major sources of liver cholesterol

• Dietary cholesterol
• Chylomicron remnants
• Cholesterol from extrahepatic tissues
• HDL
• De novo synthesis in the liver from carbs, lipids & proteins
• Major routes by which cholesterol leaves the liver
• Secretion of VLDL
• Free cholesterol secreted in bile
• Conversion to bile acids/salts
• Intake + synthesis = ~1 g/day

Endogenous Cholesterol Synthesis

• Made in the liver & intestines
• HMG CoA reductase – rate limiting enzyme (-)

Cholesterol Functions

• Cell membrane integrity
• Required for
  • Steroid hormones
  • Bile
  • Vitamin D
• Only found in animal products!!

Plasma Membrane

• Hydroxyl group on cholesterol is facing the same direction as the polar head group

Steroid Hormones Types

• Sex hormones
  • Androgens (Ex. Testerosterone)
    • Promote muscle development
    • Spermatogenesis
  • Estrogens (Ex. Estradiol)
    • Regulation of menstrual cycle
  • Progestagens (Ex. Progesterone)
    • Suppresses ovulation
    • Implantation & maturation of fertilized ovum
• Corticosteroids
  • Glucocorticoids (Ex. Cortisol)
    • Mediators of inflammation
    • Increased gluconeogenesis
    • Break down muscle protein
  • Mineralocorticoids (Ex. Aldosterone)
    • Regulates Na+/K+ balance

Bile Acids

• Cholic acid (cholate)
• Cholesterol 7-α-hydroxylase (-)
• Type of cytochrome P450 enzyme

Bile Salts

• Bile Salts = Conjugated Bile Acids
  • Bile acid + glycine $\rightarrow$ Glycocholate
  • Bile acid + taurine $\rightarrow$ Taurocholate

Bile

• Bile is efficiently reabsorbed in the ileum (95%)
• 5% that is not absorbed ends up in the feces
• 15-30g bile salts secreted daily
• ~0.5g lost in feces daily
  • ONLY mechanism for cholesterol excretion!!
• ~0.5g new bile made daily
• Bile acid binders used in cholesterol treatment

Vitamin D Synthesis

• 7-dehydrocholesterol $\xrightarrow{UVB}$ previtamin D3 $\rightarrow$ Vitamin D3 (inactive) $\rightarrow$ Calcidiol $\rightarrow$ Calcitriol
  hydroxylase hydroxylase

Cholesterol: Free Cholesterol vs. Cholesterol ester

• Cholesterol ester: Storage form less polar & more hydrophobic

Cholesterol: Free Cholesterol and Plant sterols

• Plant sterols compete with cholesterol for absorption & can be used to treat hypercholesterolemia.

Lipid Functions

• Storage
  • Lipids are 80% of