M2C Unit 2 Lesson 13 and 14

Trans fatty acids ___ LDL and __HDL

increase ; decrease

/Which fatty acids do we need?

Linoleic Acid and Linolenic Acid

Linoleic acid

18 carbons, 2 cis double bonds, ω-6 fatty acid

Linolenic acid

18 carbons, 3 cis double bonds, ω-3 fatty acid

Fatty acids are stored as neutral lipids called?

triaclyglycerols (TGs)

TGs are very hydrophobic, and are stored in cells in an anhydrous form

fat droplets

Three major classes of plasmalogens

choline, ethanolamine and serine.

What is platelet activating factor, PAF?

choline plasmalogen inducing cellular responses at concentrations as low as 10-11 M and a mediator of hypersensitivity, acute inflammatory reactions and anaphylactic shock.

The synthesis and release of PAF from cells leads to?

platelet agresssion and release of serotonin from platelets

Aspirin alleviates pain, fever, and inflammation by inhibiting the synthesis of?

prostaglandins

What are Eicosanoids?

used as a collective name for molecules derived from 20-carbon fatty acids.

The eicosanoids consist of?

• Prostaglandins (PGs)

• Thromboxanes (TXs)

• Leukotrienes (LTs)

What are eicosanoids consist of ( Prostaglandins (PGs), Thromboxanes (TXs) , Leukotrienes (LTs))

These are locally acting, hormone-like lipids derived from dietary essential unsaturated fatty acids that are important drug targets

Prostaglandin E2 role

an cause constriction of blood vessels

Role of Thromboxane A2

involved in blood clot formation

Role of Leukotriene D4

mediator of smooth-muscle contraction and bronchial constriction seen in asthmatics

What are Cyclooxygenase (COX) enzymes?

part of the ; arachidonic acid pathway convert: arachidonic acid → prostaglandins and thromboxanes

What are COX involved in?

inflammation, pain, platelet aggression, renal blood flow

Cell membrane phospholipids are broken down by phospholipase A₂ to release?

arachidonic acid

Function of COX-1

Housekeeping” enzyme Normally present in many tissues all the time.

Produces prostaglandins involved in: gastric mucosal protection, platelet aggregation, and renal blood flow

Which COX enzyme makes TXA₂ (thromboxane A₂)?

COX-1

Importnace of TXA₂ (thromboxane A₂)?

vasoconstriction and platelet aggression

Which COX enzymes are inhibted by NSAIDs?

COX 1 and 2

Aspirin irreversibly inhibits what in platelets?

COX-1 (decreasing platelet aggression)

COX-2 function

inducible inflammatory enzyme

• upregulated by:

  • inflammation

  • injury

  • infection

COX-2 produces prostaglandins causing?

• pain

• fever

• inflammation

Importance of Prostacyclin (PGI₂)?

• vasodilation

• inhibits platelet aggregation

What COX enzyme produces Prostacyclin (PGI₂)?

COX-2

coxib is an inhibitor for which COX enzyme?

COX-2

COX-3 function

COX-3 is less clinically important and somewhat controversial.

• splice variant of COX-1 and mainly involved in brain/CNS

• helps to mediate pain and fever (in the brain)

What COX enzyme is inhibited by Paracetamol?

COX-3

A hormone-sensitive lipase converts TGs to?

free fatty acids and glycerol

At low carbohydrate and insulin concentrations, TG hydrolysis is stimulated by increased?

epinephrine ((binds to b-adrenergic receptors, and activates

cAMP-dependent protein kinases)

What is the b-oxidation pathway?

degrades fatty acids two carbons at a time

What are the three stages of the b-oxidation pathway?

1) Activation of fatty acids in the cytosol

(2) Transport into the mitochondria

(3) Degradation to two-carbon fragments (as acetyl CoA) in the mitochondrial matrix

Reaction that uses Acyl-CoA Synthetase?

Fatty acid + ATP + CoASH <=> Acyl-CoA + AMP + PPi

Reaction that uses Carnitine Palmitoyltransferase?

Acyl-CoA + Carnitine <=> Acyl-Carnitine + CoASH

Reaction that uses Acetyl-CoA Carboxylase?

Acetyl-CoA + ATP + HCO3- <=> Malonyl-CoA + ADP + Pi

Malonyl-CoA effect on fatty acid oxidation?

inhibits CPT-I

Fatty Acid Synthetase reaction

Acetyl-CoA + 7 Malonyl-CoA + 7 NADPH → Palmitate + 7 CoASH + 7 CO2 + 7 NADP+ + 7 H+

Importance of the Carnitine shuttle?

Long-chain fatty acids cannot cross inner mitochondrial membrane

CPT-I (Carnitine palmitoyltransferase I) location

outer mitochondrial membrane

CPT-I function

Transfers fatty acyl group:

• CoA → carnitine

and makes acyl-carnitine

Malonyl CoA levels in fasting or diabetes

low = low acetyl-CoA = high CPT activity

Antiport protein function

moves acetyl-carnitine into mitochondria matrix and carnitine out to the cytosol

CPT-II location

inner mitochondrial membrane

CPT-II function

breaks down acyl-carnitine to acyl-CoA + carnitine and regenerates fatty acyl-CoA

Where does acetyl-CoA go after fatty acid oxidation?

beta oxidation

Fatty acids in the cytosol are activated by conversion to CoA thioesters by?

acyl-CoA synthetase (ATP dependent)

Net of ___ ATP equivalents are consumed to activate one fatty acid to a thioester

two

The carnitine shuttle system transfers long-chain fatty acyl CoA from the cytosol into

the mitochondria

The liver isoform (CPT1A or CPTI-L) for CPT-I?

is found throughout the body on the mitochondria of all cells except for skeletal muscle cells and brown adipose cells.

The muscle isoform (CPT1B or CPTI-M) of CPT-I

is highly expressed in heart and skeletal muscle cells and brown adipose cells

The brain isoform (CPT1C) CPT-I

was isolated in 2002. It is expressed predominantly in the brain and testes

CPT1C involvement in the regulation of peripheral metabolism

CPT1C KO mice fed a HFD show reduced FAO in muscle and liver and impaired glucose homeostasis, resulting in an obese phenotype with insulin resistance

CPT1C Effect on neuronal metabolism

• No effect on CPT activity or FAO

• increased lipid droplets (TAG)

• increased Caramides

• increased Endocannabinoids

• decreased elongation of unsaturated long chain FA

CTP1C physiological functions in the brain

• control food intake

• regulation of peripheral metabolims

• sparial learning

• motor function

At the molecular level, CPT1C is located in the ER and is able to

bind malonyl CoA

At the cellular level, CPT1C is involved in

various lipid metabolic pathways and the redox homeostasis system

At the physiological level, CPT1C is involved in

several brain functions

What is The "CPT1A" form is associated with CPT-I deficiency

rare disorder confers risk for hepatic encephalopathy, hypoketotic hypoglycemia, seizures, and sudden unexpected death in infancy

3 main types of CPT-II deficiency

• Neonatal form

• Infantile form

• Adult form

Neonatal CPT-II deficiency

• least common and very fatel

• Symptomatic onset just hours after birth to within 4 days of life.

• Affected newborns typically experience respiratory failure, low

blood sugar, seizures, liver enlargement, liver failure, heart

enlargement with abnormal heart rhythms leading to cardiac

arrest

Infantile CPT-II deficiency

• Symptomatic presentation usually occurs between 6 and 24

months of age.

• Involves multiple organ systems and is primarily characterized

by hypoketotic hypoglycemia that often results in loss of

consciousness and seizure activity.

• Acute liver failure, liver enlargement, and cardiomyopathy.

• Episodes are triggered by febrile illness, infection, or fasting.

• Some cases of sudden infant death syndrome are attributed to

infantile CPT II deficiency at autopsy

Adult CPT-II deficiency

• Exclusively myopathic form is the most prevalent and least

severe phenotypic presentation.

• Characteristic signs and symptoms include rhabdomyolysis

(breakdown of muscle fibers and subsequent release of

myoglobin), myoglobinuria, recurrent muscle pain, and

weakness.

• The myoglobin release causes the urine to be red or brown and is

indicatory of damage to the kidneys, which ultimately could

result in kidney failure.

• Muscle weakness and pain typically resolves within hours to

days, and patients appear clinically normal in the intervening

periods between attacks.

What is b-oxidation?

One round of β-oxidation consists of 4 enzyme steps that produce acetyl-CoA from fatty acyl-CoA

Each round of beta-oxidation generates one molecles each of?

FADH2 (QH2)

NADH

Acetyl CoA

Fatty acyl CoA (2 carbons shorter each round)

Cycles of ß-Oxidation

the # of carbons / 2-1 = # of cycles

amount of Acetyl CoA produced

the # of carbons/2

balanced equation for oxidizing one palmitoyl CoA by seven cycles of b oxidation

Palmitoyl CoA + 7 HS-CoA + 7 FAD + 7 NAD+ + 7 H2O → 8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+

1 acetyl CoA = __ ATP?

10

What are Ketone Bodies?

During fasting or starvation, glucose is decreased, and excess acetyl CoA from fat metabolism can be converted to this

• Ketone bodies can fuel brain cells during starvation

Ketosis

ketone body accumulation with acidic ketone bodies lowering blood pH to <7.4

b-Oxidation of Odd-Chain FA final cleavage poduct?

propionyl CoA rather than acetyl CoA

b-Oxidation of Unsaturated FA, degradation requires which two other enzymes in addition to the b-oxidation pathway enzymes

(1) Enoyl-CoA isomerase

(2) 2,4-Dienoyl-CoA-reductase