619 GLA 8/12 Lipid Metabolism

Where and in what state does fatty acid synthesis occur in?

it occurs in the liver in the fed state

Fatty Acid Synthesis (simple)

conversion of acetyl CoA to fatty acids

monosaccharides, ethanol, and most amino acids are all potential carbon sources

What are the sources of carbs for fatty acid synthesis?

excess dietary carbs are the primary source, excess dietary proteins can also contribute

What other cycle is fatty acid synthesis dependent on?

TCA Cycle

Linkage of Fatty Acid Synthesis to TCA Cycle

fatty acid synthesis occurs in the cytosol, but acetyl CoA is produced in the mitochondria and can’t pass membranes

citrate shuttles the excess acetyl CoA to the cytosol

Cytosol

location of fatty acid synthesis

Citrate

shuttle that transports acetyl CoA to cytosol for fatty acid synthesis

Isocitrate Dehydrogenase

controls the extent to which citrate leaves the mitochondria when transporting acetyl CoA to the cytosol

Isocitrate Dehydrogenas Inhibitors

ATP and NADH

Isocitrate Dehydrogenase Activators

ADP and Ca+2

Pyruvate Carboxylase

converts pyruvate → oxaloacetate

replenishes the TCA cycle intermediates that are lost to fatty acid synthesis so the cells ability to make ATP is not compromised

Diagram of Where Fatty Acid Synthesis Is

TCA Cycle Linkage to Fatty Acid Synthesis Diagram

Where does beta-oxidation occur?

it occurs in the mitochondria

Why is it important for beta-oxidation and fatty acid synthesis to be in different parts of the cell?

it prevents the fatty acids synthesized from immediately being broken down by beta-oxidation and vice versa

Citrate Lyase

converts citrate carrying acetyl CoA into acetyl CoA in cytosol

Oxaloacetate

element of TCA cycle that needs to be replenished by puruvate carboxylase

NADPH

synthesized from pentose phoaphate pathway, required for fatty acid synthesis

Glucose-6-Phosphate Dehydrogenase

enzyme is pentose phosphate pathway that generates NADPH

Preperatory Phase of Fatty Acid Synthesis

NADPH generation in the pentose phosphate pathway by the enzyme glucose-6-phosphatedehydrogenase

expression of malic enzyme in the liver to generate NADPHby converting malate → pyruvate

NADPH Synthesis for Fatty Acid Synthesis Diagram

3 Simple Steps of Fatty Acid Synthesis

acetyl CoA is converted to malonyl Coa by acetyl CoA carboxylase

malonyl CoA is converted to palmitate by fatty acid synthase

elongation, desaturation, and triglyceride synthesis occur

Fatty Acid Synthase

converts malonyl CoA to palmitate in fatty acid synthesis, requires biotin

Acetyl CoA Carboxylase

converts acetyl CoA to malonyl CoA in fatty acid synthesis, highly regulated step of fatty acid synthesis, requires biotin

Acetyl CoA Carboxylase Stimulants

insulin, citrate, and a high calorie diet

Acetyl CoA Carboxylase Repressors

palmitoyl CoA and AMP

Palmitate

16 carbons, initial product of fatty acid synthesis that is then changed

Fatty Acid Synthesis Diagram

What cofactor do all carboxylase enzymes require?

biotin

Biotin

cofator of carboxylase enzymes, found in many foods and can be synthesized by some intestinal bacteria so deficiency is very rare

What can cause biotin deficiency (rare)?

antibiotic use and excessive raw egg consumption

Biotin Deficiency Clinical Presentation

mental status changes, dermatitis, and alopecia

How do eggs cause biotin deficiency?

they contain the protein avidin which binds to biotin and inhibits its absorption

When is fuel storage regulated to occur in?

the fed state

What enzymes are more active for fatty acid synthesis when the insulin/glucagon ratio is high?

g6pd, citrate lyase, malic enzyme, acetyl CoA carboxylase, fatty acid synthase

What three regulated glycolytic enzymes in the liver are more active when the insulin/glucagon ratio is high?

glucokinase

pfk-1

pyruvate kinase

Malonyl CoA

part of fatty acid synthesis pathway, inhibits beta-oxidation to prevent a futile cycle

Lipolysis Diagram

Beta-Oxidation

breakdown of fatty acids to form glucose

When does beta-oxidation of lipids occur?

fasted state

When does beta-oxidation of muscle occur?

fed and fasted state

Fatty Acid Catabolism (Beta-Oxidation) Depends Partially on FA Chain Length and Structure

very long chains (>20C), long chains (12-20C), medium chains (6-12C), short chains (4C)

branched or unbranched

saturated or unsaturated

What is the structure of most FAs released from adipose and ingested?

long-chain unbranched

Where does beta-oxidation occur?

mitochondria

Beta-Oxidation Diagram

What types of tissues can get energy from fatty acids?

only aerobic tissues can get energy from fatty acids

Beta-Oxidation Basics

fatty acyl-CoA synthase “activates” the fatty acids

carnitine facilitates transport across the mitochondrial membrane

the beta-oxidation spiral slowly cuts it up more and more to produce NADH, FADH2, and acetyl CoA so the TCA cycle and oxidative phosphorylation must be active in order to generate ATP from fatty acids

3 Products of Beta-Oxidation

acetyl CoA, NADH, FADH2

Carnitine

a necessary cofactor for transport of most fatty acids to the mitochondria

Diagram of Transfering Acetyl CoA into the Mitochondrial Matrix

4 Steps of Transferring Acetyl CoA into the Mitochondrial Matrix

carnitine palmitoyl transferase 1 (CPT1) transfers the fatty acid from CoA to carnitine forming acylcarnitine

the acylcarnitine is translocated across the inner membrane and CPT II transfers the fatty acid back to CoA (takes off carnitine)

carnitine is shuttled back across the inner membrane

acyl CoA is in the mitochondrial matrix for beta-oxidation

Carnitine Palmitoyl Transferase 1 (CPT1)

in the outer mitochondrial membrane, transfers the fatty acid from fatty acid CoA to carnitine forming an acylcarnitine

CPT II

in the inner mitochondrial membrane, converts acylcarnitine to acetyl CoA in mitochondrial matrix

What does CPTII Deficiency Cause

acylcarnitine build up in the inner mitochondrial space

Beta-Oxidation Spiral

breakdown of acetyl CoA in the mitochondrial matrix, acyl-CoA dehydrogenases are involved

Acyl-CoA Dehydrogenases (CADs)

key enzymes in spiral of beta-oxidation, catalyze the first step in each beta-ox cycle

transform palmitoyl CoA → 7 acetyl CoA

How are Acyl-CoA Dehydrogenases classified?

they are classified based on their substrate specificity

Two Types of Acyl-CoA Dehydrogenases

long-chain acyl-CoA dehydrogenase (LCAD)

medium-chain acyl-dehydrogenase (MCAD)

CAD Deficiency

leads to an inability to complete beta-oxidation

Will acylcarnatines accumulate in patients with MCAD or LCAD deficiencies?

yes, because even though CPTII is still able to take off the caratine, there is a backup of the fatty acids in the matrix, which limits CPTII activity

Do hormones regulate beta-oxidation?

no, hormones do not directly regulate beat-oxidation

What is the key factor to determining the rate of beta-oxidation?

substrate availability (substrate is fatty acids)

What inhibits beta-oxidation?

it is inhibited by malonyl CoA which blocks CPTI to ensure that newly synthesized fatty acids are not transported to the mitochondria for beta oxidation

Hormone Sensitive Lipase

controls the availability of substrate (fatty acids) for beta oxidiation in the fasted state

Systemic Primary Carnitine Deficiency

an inherited disorder caused by a mutation in the protein that transports carnitine into cells

Carnitine Importance

without carnitine, fatty acids cannot enter the mitochondria and acumulate causing cell damage

2 Other Pathways of Fatty Acid Oxidation

peroxisome (long-chain fatty acids)

omega oxidation

Omega Oxidation

in the ER, generates dicarboxylic acids which may be detected in blood and urine in patients with impaired beta-oxidation