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22 Cards in this Set

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What is the Importance of Fatty Acid ß-Oxidation?
-Chemical potential energy (storage)

-Predominant source of energy production (60-80% of 2000 kcal/day)

Disorders
-Muscles without B-oxidation are dysfunctional.
-Metabolic syndrome, obesity and insulin resistance
Where do the fatty acids come from?
1. Dietary lipids
-Triacylglycerol
-Phospholipids
-Cholesteryl esters

2. Circulating serum lipoproteins (VLDL, LDL, chylomicrons, HDL)

3. Intracellular stores
-Adipose tissues
-Cytoplasmic lipid droplets
-Membranes
Describe mos eof the sources of fatty acids?
-inert

-hydrophobic complex lipids

-NOT substrates for Beta oxidation
STEP 1 - LIPOLYSIS
-Lipases hydrolyze one or more ester bonds to release unesterified fatty acids.

-There are 3 major classes of triglyceride lipases:
Pancreatic lipase
Lipoprotein lipase
Hormone sensitive lipase
What are the major classes of Triglyceride Lipases?
1. Pancreatic lipase
-stimulated by bile acids

2. Lipoprotein lipase
-stimulated by insulin

3. Hormone sensitive lipase
-activated by glucagon (cAMP)
Where/When are pancreatic and lipoprotein lipases involved?
Pancreatic and Lipoprotein lipases are important for lipid digestion and transport.
What are some common lipid hydrolyzing specific lipolytic enzymes?

Remember that phospholipases are important in signaling pathways and digestion.
Phospholipases
-PLA1
-PLA2
-PLC
-PLD

Know where each of these enzymes cleave for a triglyceride.
Cholesterol

STEP 2 - TRANSPORT
Esterified fatty acids - in lipoproteins (VLDL, chylomicrons)

Unesterified fatty acids – serum albumin and other fatty acid binding proteins

Across membranes – fatty acid transport proteins and shuttles
Unesterified fatty acids are not substrates for Beta oxidation. What do most pathways require for metabolization?
Most pathways that metabolize fatty acids require activation to fatty acyl-CoA.
STEP 3 – ACTIVATION (outer mitochondrial membrane, endoplasmic reticulum)
fatty acyle-CoA synthetase uses an ATP to join the subunits together.

The reaction is made irreversible by coupling to pyrophosphatase conversion of PPI to 2Pi.

The carnitine shuttle delivers the product to the mito Matrix
What is the function of Malonyl CoA
Malonyl CoA is the product of acetyl-CoA carboxylase, rate-limiting enzyme in fatty acid synthesis.

ACC isoforms regulate the level of malonyl CoA in response to changes in metabolic/energy status (e.g., availability of substrates, need for energy).
What is the role of medium chain fatty acids in Activation?
Medium chain fatty acids are poor substrates for the fatty acyl-CoA synthetases on the outer mitochondrial membrane, but good substrates for the corresponding enzyme in the matrix.

Consequently, medium chain fatty acids remain unesterified and do not require the carnitine shuttle for transport across the mitochondrial membrane.
Match to a description:

1. esterified fatty acids (diet, blood, cell)

2. unesterified fatty acids (intestine, Blood, cell)

3. mitochondrial matrix
1. Insoluble lipids

-->lipolysis

2. Toxic fatty acids

-->transport

3. site of beta-oxidation
STEP 5 -- b-OXIDATION

What is it regulated by?
Source and availability of fatty acids (lipase activity)

Transport across the mitochondrial membrane (rate-limiting under many conditions)

Activity of enzymes in the pathway (regulation at the transcriptional level)
Trace the breakdown of fat stores and the associated enzymes and systems.
1. Intracellular fat stores
-->lipase
2. Extracellular fatty acid
-->Carnitine shuttle (CAT I)
3. Mitochondrial fatty acid
-->Enzymes of B-oxidation
4. Acetyl-CoA
5. Ketogenesis or TCA
B-Oxidation is mediated by nuclear transcription factors. Describe their actions on the specific systems and enzymes.

Basically, how does the FA get into the cell.
1. Lipase - Covalent Modification
-increase with glucagon
-decrease with insulin

2. Carnitine Shuttle - Allosteric inhibition
-decrease with malonyl-CoA

3. Enzymes of B-Oxidation - Transcriptional Regulation
-increase with fatty acid hormones
What are the effectors for regulation of fatty acids?
The effectors can be fatty acids, carbohydrates, hormones and/or drugs.
THE FAT ECONOMY

Fasting
High fat, low carbohydrate diets
Diabetes
In each of these states, insulin activity is low, relative to glucagon.
Glucogenic versus Ketogenic
Any intermediate in the TCA cycle can be converted to oxaloacetate, which is a potential substrate for gluconeogenesis.

Acetyl CoA is burned by the TCA cycle; it is not an intermediate.

In mammals, there is no pathway for conversion of acetyl CoA into an intermediate in the TCA cycle or gluconeogenesis.

Therefore, excess acetyl CoA is converted into acetoacetate.
Physiological Importance of Ketogenesis
Sink for excess acetyl-CoA

Easily utilized energy source for peripheral tissues

Primary energy source for brain during prolonged fasting
Medical Significance of Ketogenesis

It is important to distinguish between uncontrolled ketosis of diabetes (DKA), and ketosis as a normal compensatory response to fasting or low carbohydrate intake.
Major manifestation of uncontrolled diabetes (ketosis, ketonuria, acetone breath)

Effects on acid-base balance (acidosis) - as affected by lipid metabolism

Depletion of essential cations
An Alternative Pathway for β-Oxidation of Very Long Chain Fatty Acids (>20C)
Mitochondria are unable to oxidize fatty acids >20C.

High concentrations of these fatty acids in the diet will stimulate proliferation of peroxisomes with an alternative oxidative pathway.

Peroxisomes oxidize the first few carbons from a fatty acid, converting it to a substrate for the mitochondrial pathway.