Comprehensive Lipid Metabolism: Triglycerides, Beta-Oxidation, and Ketogenesis 낱말 카드

What is the structure of triglycerides (fats)?

3 fatty acids esterfied to a glycerol backbone

What is the function of triglycerides?

Storage and transport form of lipids

Where are triglycerides mainly found?

Adipose tissue

Triglycerides are a major energy source for what?

Liver, muscle, and tissues

Triglycerides are NOT a major energy source for what?

Red blood cells and brain

84% of energy is stored in ____.

Fats

Fats are transported using __________.

Chylomicrons (plasma lipoproteins)

Fats are hydrolyzed by lipases releasing ________, which are taken up by cells.

Glycerol and fatty acids

Glycerol is converted to glyceraldehyde phosphate that is converted into ________ that enters the TCA cycle.

Acetyl-CoA

What process do fatty acids go through to produce Acetyl-CoA and reduced nucleotides?

Beta oxidation

What products are formed by the beta-oxidation of fatty acids from triglycerides?

Acetyl-CoA, FADH2, and NADH

What cycle does Acetyl-CoA enter?

TCA

What cycle does FADH2 and NADH enter?

ETC

How is Acetyl-CoA metabolized in muscle?

TCA cycle and oxidative phosphorylation to produce ATP

How is Acetyl-CoA metabolized in the liver?

Converted to ketone bodies via ketogenesis

What is produced by ketogenesis and is a water-soluble lipid derivative that's exported to other tissues?

Ketone bodies

What controls fat metabolism?

Triglyceride hydrolysis rate in adipose tissue

Triglyceride hydrolysis in adipose tissues is regulated by ___________.

Hormones (ex. insulin, glucagon)

Fatty acids will not be found free floating in the body, so they will be found as _______ or attached to _______ in the blood.

Soaps, plasma albumin

To enter beta oxidation, fatty acids need to be _________.

Activated

Fatty acids are activated to form CoA derivatives using ATP. These reactions are catalyzed by ____________.

Fatty acyl-CoA synthetase

Which FAs are able to cross the mitochondrial membrane by diffusion and are activated in mitochondria?

Short and medium chain

Which FAs are activated in the cytoplasm and transported via the carnitine shuttle?

Long chain

Where are very long chain FAs shortened to long chain FAs?

Peroxisomes

12-20 carbon length acyl-CoA are too ________ and ________ to penetrate the inner mitochondrial membrane.

Large and polar

What allows the transfer of fatty acyl-CoAs into mitochondria, where beta oxidation can occur?

Carnitine shuttle

How does beta oxidation of fatty acids occurs?

Oxidation of beta- carbon (to keto group) then cleavage between alpha- and beta- carbons

Where beta oxidation of fatty acids occur?

Mitochondria

What is released each turn of cycle of beta oxidation of fatty acids?

Release of two-carbon acetyl-CoA units

What is ketogenesis?

Metabolic process unique to liver

What level are the fat derived ATP and NADH concentrations during fasting/starvation?

High in mitochondria

What does oxaloacetate do during fasting?

malate equilibrium shifted towards malate and then Malate enters gluconeogenesis pathway

What does limited oxaloacetate mean?

Limited oxaloacetate results in limited TCA cycle activity

What happens to Acetyl-CoA during fasting?

it accumulates

What gets rid of excess acetyl CoA?

Liver

What is CoA is essential for?

Beta- oxidation

- it limits beta-oxidation of fatty acids and is the primary source of ATP in liver

Ketogenesis

Acetyl-CoA must be recycled to regenerate free CoA

________ is generated and acetate ends up as acetoacetate, beta-hydroxybutyrate, and acetone (ketone bodies)

Free CoA

During starvation, brain uses ketone bodies for

> 50% of energy metabolism

Starvation spares glucose and degradation of muscle protein for what?

gluconeogenesis

What is ketonuria?

When ketone bodies are in the urine and this occurs with high-fat and low card diets

What can ketonuria cause?

May cause metabolic acidosis (too much acid in blood)

Most fatty acids are supplied in the

diet

When does lipogenesis occur?

During excess energy/carbohydrate intake

What is the main lipogenic organ?

Liver

Defects of lipogenesis aren't life-threatening but they play a role in what?

Obesity

Carbohydrate converted to fatty acids in the ________ and stored as triglycerides in ___________

liver, adipose tissue

What does lipogenesis (fatty acid synthesis require?

Requires different set of enzymes located in the

cytosol (not mitochondrion)

Fatty acids are synthesized from acetyl-CoA in a ______-stage process

2

What is the first stage of lipogenesis?

formation of malonyl-CoA from acetyl-CoA by acetyl-CoA carboxylase

What is stage 2 of lipogenesis?

elongation of the fatty acid chain in two- carbon increments by fatty acid synthase

What is Acetyl-CoA Carboxylase?

Biotin-dependent enzyme

Where is Acetyl-CoA Carboxylase produced?

in an inactive "promoter" form containing 3 subunits

What are the three subunits?

1. Biotin carboxylase

2. Transcarboxylase

3. Biotin carboxyl carrier

◦ AND regulatory site for binding citrate (TCA cycle) or palmitoyl-CoA (end product of lipogenesis)

What is step 1 in the first stage of lipogenesis?

Carboxylation of biotin, with ATP input

What is step 2 in the first stage of lipogenesis?

Transfer of carboxyl group to acetyl-CoA to produce malonyl-

CoA

What is step 3 in the first stage of lipogenesis?

Release of free enzyme-biotin complex

Acetyl-CoA carboxylase requires ______ for polymerization to active form. And what is this inhibited by?

citrate/isocitrate and Inhibited by palmitoyl-CoA (end-product)

Acetyl-CoA carboxylase is activated by ________.

Dephosphorylation - Promoted by insulin, which is a lipogenic hormone

Acetyl-CoA carboxylase is inhibited by ________.

Phosphorylation - Promoted by glucagon or epinephrine

Acetyl-CoA is committed to fatty acid synthesis when it is converted to _________.

Malonyl-CoA- this is strict short term control

What includes the longer term control of acetyl-CoA carboxylase synthesis?

- Upregulated - high-carbohydrate/low-fat intake

- Downregulated - starvation or high-fat/low- carbohydrate intake

What is the second step of lipogenesis?

Elongation of fatty acid chain in 2-carbon increments via fatty acid synthase

During the second stage of lipogenesis, what replaces the CoA on malonyl-CoA?

Acyl Carrier Protein (ACP)

Fatty acid synthase builds up the fatty acid chain to ___ carbons long.

16

What are the 2 components of fatty acid synthase?

7 enzyme activities and ACP

Dimer of identical polypeptides arranged __________

head to tail

What are the FA synthesis functions shared between?

the two polypeptide

chains

What does each monomer contain?

7 enzyme activities and ACP

In fatty acid synthase, what acts as a flexible arm making the molecule being synthesized available to different enzymes?

Long pantethein group

Fatty acid synthesis is regulated by allosteric effects on the enzyme by various ____________.

Phosphorylated sugars

Rate of FA synthesis is lowest for _________ diets and low during _______.

low fat/high carb, fasting or high fat diets

Fatty acid biosynthesis occurs in the _________.

Cytosol

Primary molecule required for the synthesis of fatty acids is what?

acetyl-CoA

Acetyl-CoA is formed in the mitochondria but cannot cross the membrane to enter the cytosol. The _______ allows for transport of two-carbon units from the mitochondria to cytosol.

Malate shuttle

What pathway links fatty acid synthesis to glucose metabolism?

Pentose Phosphate Pathway

What is the function of the pentose phosphate pathway?

Produce NADPH for lipogenesis

Fatty acid synthase builds the fatty acid molecule up to

16-carbons in length

What fatty acids are needed in the body?

Longer fatty acids are needed by the body

◦ Example: Very long-chain (22-24-carbon) fatty acids are produced in the brain

Fatty acid synthesis builds molecules up to 16 carbons in length but the body needs longer ones so ___________ must occur.

Elongation

What enzyme is used in fatty acid elongation?

elongase

Fatty acid elongation is similar to synthesis (Reduction, Dehydration, Reduction) except the fatty acid is attached to _______ rather than ACP.

CoA

Fatty acid elongation occurs typically occurs in __________ and is carried out by fatty acid elongase (multienzyme complex)

endoplasmic reticulum

What other fatty acids does the body require?

The body also requires mono- and polyunsaturated fatty acids

◦ Some of these are supplied in the diet: essential fatty acids (linoleic and linolenic)

◦ Some are not supplied in the diet and require desaturation of fatty acids

What 3 components are needed to desaturate fatty acids?

Oxygen, NADH, Cytochrome b5

Where does fatty acid desaturation take place?

Endoplasmic reticulum and results in oxidation of both the fatty acid and NADH

How does denaturation explain why some fatty acids are essential?

Desaturase system is unable to introduce double bonds between

carbon atoms beyond carbon-9 and the ω (terminal methyl)\

FAs (either from diet or synthesis) are stored and transported as ________

triacylglycerols

What needs to happen before triacylglycerols can be used to store and transport FAs?

First, triacylglycerols need to be synthesized from FAs

What are Triglycerides synthesized in the liver and in adipose tissue from?

glycerol-3-P

◦ Phosphatidic acid intermediate

Does triacylglycerol synthesis require glycerol kinase in the liver or in adipose tissue?

Liver

Are triacylglycerols stored in the liver or in adipose tissue?

Adipose tissue

Triacylglycerols are exported by the liver and complexed with cholesterol, and phospholipids, and apolipoproteins to form __________.

VLDL

VLDL in blood is processed and released into bloodstream for?

uptake by other tissues

What is the function of lipoprotein lipase?

Degrades VLDL

How does LPL vary in muscle?

very low Km for substrate - active on VLDL at very low concentrations

How does LPL vary in adipocyte?

high Km for substrate - only active when VLDL concentrations are elevated

What directs fat metabolism toward synthesis and storage?

Insulin

What does insulin stimulate?

- Stimulates glycolysis in the liver, increasing pyruvate production

- Insulin also activates (via dephosphorylation) pyruvate dehydrogenase to promote production of acetyl-CoA

What does insulin promote in fat cells?

insulin promotes acyl-coA Formation → triacylglycerols