Lipids I: Fatty Acids and Triglyerides - COMPLETE!!!

Question 1

What are the general properties of lipids?

Answer 1

General properties of lipids

• heterogeneous
• ampiphatic
• hydrophobic
• compartmentalized in membranes, triglyceride droplets, or lipoprotein particles

OR

-associated wtih Albumin (lipid transport protein)

Question 2

What is are the metabolic functions of fatty acids?

Answer 2

Fatty Acid (FA) Function:

• major long-term storage of energy in body (weeks) (Glycogen is short-term storage, 12 hrs)
• major endogenous source during Fasting States… during Fasting States, many tissues use FAs as fuel rather than than Glycogen/Glucose…this reserves Glucose for the brain
• FAs more reduced than Glucose, and therefore yield more energy per given mass (9 kcal/g for FA, 4.1 kcal/g for Glc)
• FAs are oxidized through β-oxidation, producing Acetyl-CoA which can enter TCA Cycle –> oxidative phosphorylation
• Note: B-oxidation can also be converted to Ketone Bodies, a fuel source for the brain

Question 3

What is the structure of FAs?

Answer 3

Question 4

What are the three nomenclature systems of FAs?

Answer 4

SYSTEM 1:

COOH C = “C1”

C2 = α-C

C3 = β-C

terminal C = Ω-C

“18:0” –> 18 C’s, no double bonds (saturated FA)

“18:2(Δ9,15) –> 18 C’s, 2 double bonds (one betw C9-C10, the other between C15-C16)

SYSTEM 2: Chemical Names / Common Names

ie: cis-9-octadecenoic acid (chemical name)
ie: Stearate (common name)

“-anoic acid” –> saturated FA

“-eoic acid” –> unsaturated FA

SYSTEM 3: Omega FAs: FAs numbered from their terminal Ω-C (becomes “C1”), the double bond is indicated using this scheme

Omega FAs tend to be Ω-3, Ω-6, Ω-9, Ω-12, Ω-15 FAs and so on

Question 5

What are Saturated FAs? What is their clinical significance?

Answer 5

Saturated FAs = FAs in which all Cs are completely reduced (no double bonds)

-b/c they are unkinked, they pack more closely together and therefore have a HIGHER melting pts (tend to be solid at room T)

Saturated FAs increase risk of

• atherosclerosis
• coronary heart disease
• stroke
• negative cholesterol profile

AHA recommends FAs should be < 7% of daily caloric intake.

Most Common Saturated FAs:

• Palmitic Acid (C16:0) - found in meat and palm oil
• Stearic Acid (C18:0) - found in meat and cocoa butter

Question 6

What are Unsaturated FAs? What is their clinical significance?

Answer 6

Unsaturated FAs = FAs in which one (monounsaturated) or more (polyunsaturated) C’s is part of a double bond

-b/c double bonds introduce “kinks” in their tails, they cannot pack together as closely; they have LOWER melting pts than their saturated counterparts, and tend to be liquid at room T

GENERAL RULE

Animal sources tend to contain saturated FAs and monounsaturated FAs

Vegetables, seafoods, and fish oils tend to contain polyunsaturated FAs

Question 7

What are trans-fats, and what is their clincal significance?

Answer 7

Trans-fats are FAs with tran-double bonds, formed through the process of hydrogenation (for food preservatives)

• Hydrogenation used to reduce cis-double bonds of unsaturated FAs, thereby converting them to saturated FAs (in order to increase shelf life), HOWEVER, hydrogenation also increases trans-double bonds
• b/c the double bonds are trans, they do not introduce the “kink” that cis double bonds have; therefore trans FAs behave like Saturated FAs, and carry the same risks of cardiovascular disease

Question 8

What is the clinical significance of omega-FAs?

Answer 8

Ω-3 FAs and Ω-6 FAs are most clinically significant

NOTE:

Omega-3s are synthesized from other Omega-3s; Omega-6s are synthesized from other Omega-6s; both classes of omega FAs use the same enzymes

Since omega-6’s far outnumber omega-3’s in the western diet (10x-30x), often omega-3’s are outcompeted as substrates for the enzymes in rate-limiting steps for biosynthesis; therefore the omega-3s are not synthesized in great numbers and the benefits of omega-3’s aren’t often experienced (this is why fish oil, rich in omega-3s, is often taken as a supplement)

Ω-FAs found in fish, poultry, eggs, palm, soybeans, rapeseed, sunflower oils

Ω-3 FAs are known to have significant health benefits

-DHA (Docosahexaenoic Acid, 22:6(Δ4,7,10,13,16,19))

required nutrient for brain and retina for optimal neuronal functions (learning, mental development, visual acuity) at ALL developmental stages

DHA and EPA (Eicosapentaenoic Acid (20:5)

beneficial in prevention of cardiovascular disease, BT, stroke, cancer, inflammatory disease, etc

Question 9

What are the two essential FAs?

Answer 9

1) α-Linolenic acid (ALA): [18:3 (Δ9,12,15)] - an Omega-3 FA and the precursor for other Omega-3 FAs (ie DHA and EPA)
- if ALA is deficient in diet, then DHA and EPA become essential
2) Linoleic acid [18:2(Δ9,12)] - an Omega-6 FA and precursor for Arachidonic Acid, ARA
- if Linoleic acid is deficient in diet, then ARA becomes essential

Question 10

FAs I must memorize:

16:0

Answer 10

Palmitic Acid

16:0, saturated

Question 11

FAs I must memorize

18:0

Answer 11

Stearic Acid

18:0, saturated

Question 12

FAs I must memorize:

18:1(Δ9)

Answer 12

Oleic Acid

18:1(Δ9), monounsaturated

Question 13

FAs I must memorize:

18:3(Δ9,12,15)

Answer 13

α-Linolenic Acid (ALA)

18:3(Δ9,12,15)

an Ω-3, polyunsaturated FA

ESSENTIAL!!!

Question 14

FAs I must memorize:

22:6(Δ4,7,10,13,16,19)

Answer 14

Docosahexaenoic Acid (DHA)

22:6(Δ4,7,10,13,16,19)

an Ω-3, polyunsaturated FA

Question 15

18:2(Δ9,12)

Answer 15

Linoleic Acid

18:2(Δ9,12)

anα Ω-6, polyunsaturated FA

ESSENTIAL!!!!

Question 16

FAs I must memorize:

20:4(Δ5,8,11,14)

Answer 16

Arachidonic Acid (ARA)

20:4(Δ5,8,11,14)

an Ω-6, polyunsaturated FA

Question 17

How are FAs stored?

Answer 17

FAs are NOT storeed as “free FAs (FFAs); instead, they are stored as Triglycerides (TGs)

Triglyceride (TG) = Glycerol esterified to 3 FAs

Question 18

What happens to TGs during the Well-fed State?

What happens to TGs during the Fasting State/Exercise State?

Answer 18

Well-Fed State

• FAs + Glycerol –> TGs,
• TGs stored in fat droplets in Adipocytes (mostly)

Fasting State / Exercise State

• Lypolysis: TGs are hydrolyzed to Glycerol + FAs
• FAs are made available to other tissues so they can be used as energy source through B-oxidation

Question 19

What are the functions of TGs?

Answer 19

• storage form of FAs, and therefore storage form of our major energy source; TGs are less hydrated than Glycogen and therefore weigh less and and take up less space than Glyogen
• adipose tissue (filled with TG in fat droplets) helps to form protective cushion barrier for certain organs (ie kidneys)
• Thermogenesis in newborns: Brown Fat,
  
  • *Thermogenin** = protein that uncouples inner mitochondrial H+ gradient from ATP synthesis, thereby generating heat
• carrier/solvent of Fat-soluble Vitamins in their absorption in transport
• others - form precursors of vitamins, prostaglandins, etc.

Question 20

What are the four Fat-soluble Vitamins?

Answer 20

ADEK

Vitamin A

Vitamin D

Vitamin E

Vitamin K

Question 21

How are TGs digested into FAs and FAs transported to target tissues?

Answer 21

1) Ingested
2) Salivary Lipase and Gastric Lipase begin digestion of TGs in mouth and stomach (very limited)
3) When Small Intestine, Small intestine secretes hormone Cholecystokinin (CCK)

–> Gallbladder and stimulated to secrete Bile into Small Intestine

–> Pancreas stimulated to secrete Pancreatic Lipase into Small Intestine

WITHIN SMALL INTESTINE LUMINE

4) In intestine, Bile emulsifies fat, breaking large fat particles into small micelles; this increases surface area that can be contacted by Pancreatic Lipases (assists in digestion)
5) Pancreatic Lipase hydrolyzes TGs:

TG —- > 2 FFAs + Monoglyceride (monoacylglycerol)

6) FFAs and fat-soluble vitamins diffuse from micelle into intestinal mucosal cells

WITHIN INTESTINAL EPITHELIAL CELLS

7) Within the intestinal epithelial cells, FFAs are reesterified to monoglycerides, forming TGs agin

2 FFAs + Monoglycerides –> TG

8) TGs are packaged into Chylomicrons

Chylomicrons = apoliporotein complexes that transport dietary TGs to peripheral cells/tissues

• outer shell: phospholipids (hydrophilic portion), cholesterol (hydrophilic portion), Apolipoproteins
• inner core: TGs, cholesterol esters (cholesterol esterified to a FA)

OUTSIDE EPITHELIA

9) Chylomicrons travel initially in lymphatic system and then into blood stream
9) tissue cells that need FAs secrete a hydrolase Lipoprotein Lipase into capillaries; when Lipoprotein Lipase contacts the apoliprotein ApoC-II on the chylomicrons, it is activated to hydrolyze the TGs –> FFAs + Monoglycerides
10) FFAs diffuse into tissue cells; once inside, they are -reesterified back to TGs (in Adipocytes)
- Beta-oxidized for fuel (Muscle cells)

Question 22

Pathological condition:

Increase of lipids (especially fat-soluble Vitamins A, D, E, K) and essential FAs in feces

NOTE: ASK ABOUT THIS!!!

Answer 22

Steatorrhea

results from improper/defective lipid digestion or absorption

• problems with lipid digestion (Cystic Fibrosis, which causes thickened intestinal secretions)
• problems with lipid absorption (shortened/resected bowels)

Tx: dietary Medium Chain Fatty Acids and Short Chain Fatty Acids

-they don’t need to be packaged into micelles in order to be absorbed in intestine… (???)

Question 23

How are TGs synthesized?

Answer 23

Glycerolneogenesis = synthesis of Glycerol-3-Phosphate or TG from precursor other than Glucose

-occurs in Liver and Adipocytes in the Well-Fed State

2 main precursors of TG

1) Dihydroxyacetone Phosphate (DHAP), an intermediate of Glycolysis
- reduced by Glyerol-3-Phosphate Dehydrogenase to Glycerol-3-Phosphate (Glycerol-3-P)
2) Glycerol
- phosphorylated by Glycerol Kinase to Glycerol-3-P

FROM THERE

-Acyl-CoA Synthetase“activates” a FA (acyl group) by catalyzing its bonding to CoA, forming an Acyl-CoA (requires hydrolysis of ATP); then, Acyl Transferase transfers the acyl group (FA) onto Glycerol-3-P; this process is repeated (happens twice), forming Phosphatidic Acid

NOTE: Phosphatidic Acid can be used to synthesize Phospholipid

• Phosphatidic Acid Phosphatase removes the phosphate from Glycerol-3-P, converting it to 1,2-Diacylglycerol (DAG)
• acyl activation and transfer by Acyl-CoA Synthetase and Acyl Transferase occurs one more time, converting DAG to TG

Question 24

How is glycerolneogenesis different in Liver Hepatocytes and Adipocytes

Answer 24

Hepatocytes contain both Glycerol-3-P Dehydrogenase and Glycerol Kinase; therefore they can synthesize Glycerol from BOTH DHAP and Glycerol

Adipocytes contain ONLY Glycerol-3-P Dehydrogenase; therefore they can synthesize TG only from DHAP (not Glycerol)

-this makes sense, since ; if they had Glycerol Kinase, then in the Fasting State, whenver they hydrolyzed TG to FAs and Glycerol, the Glycerol would be immediately used to resynthesize TG (this would be bad… we need that FA to reach tissues that need it)

Question 25

Hormonal Regulation of TG Metabolism:

What is the Well-Fed State? What hormone is used to regulate TG metabolism in this state, and what is its effects?

Answer 25

Well-Fed State - INSULIN-mediated

(horomone levels: Insulin > Glucagon/Epi)

Goal: replenish energy stores, maintain membranes, –> synthesize phospholipids

Peripheral tissue cells: ↑ secretion of Lipoprotein Lipase

–> ↑ hydrolysis of chylomicron TGs –> ↑ intracellular FFAs –> ↑ TG synthesis

Liver Hepatocytes: ↑ synthesis of FFAs and ↑ synthesis of TGs –> TGs exported to peripheral tissue for their storage

Adipocytes:

1) ↑ secretion of Lipoprotein Lipase –> ↑ intracellular FFAs –> ↑ synthesis of TGs
2) ↓ Lipolysis (hydrolysis of existing TGs)

Muscle Cells: derive their energy primarily fro Glucose and Glycogen, NOT from TGs (there is plenty of Glucose, enough for both muscles and brain)

Question 26

Hormonal Regulation of TG Metabolism

What is the Fasting State? What hormone(s) mediates this state? What are their effects?

Answer 26

Fasting State = Glucagon / Epinephrine -mediated

(hormone levels: Glucagon > Insulin)

Goal: mobilize TG stores for peripheral tissue to use as energy, thereby reserving Glucose for brain

Peripheral tissue cells:

Adipocytes: ↑ lypolysis (mobilization of fat stores) –> FFAs enter circulation, to be used by peripheral tissue and muscle cells

Liver: ↑ oxidation of FAs –> energy used for…

↑‘d Gluconeogenesis (AAs –> Glucose, for brain)

Muscle: ↑ secretion of Lipoprotein Lipase –> ↑ intracellular FFAs –> oxidized and used as energy source (this way, Glucose is reserved for brain… in effect, source of energy for muscle shifts from glucose in Well-Fed State to FAs in Fasting State)