Fatty acid degregation updated

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Where is FA degreation take place?

Liver as it the precursor for th synthesis of ketone bodies.

What cells do not usee FA as energy during fasting?

RBC (no mito) and brain (cant pass through eh blood brain barrier)

what is the source of FAs in the fed state?

Chylomicrons —> in epithelial cells of the digestive tract

VLDL —> prod via the liver

What is the source of FAs for the fasting/excersie state?

They will use the ecxess adipose tissue to make FAs and glycerol via hormone sensitive lipase

Stimulated by evelated glucagon/insulin ratio and high epi levels

How are FAs transported and taking in when they are located int he blood?

Fed state: dietary FAs —>transported as triglycerides inside lipoproteins (chlyomicrons)

FA synthesis in the liver —> transported as triglycerides in VLDL

FAs from adipose tissue are bound to albumin

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cellular intake is done via a fatty acid binding protein int he plasma memebrane

How are FAs acitivated for metabolism

They need to be converted to fatty acyl Coa

Different enzymes depending on the size of the FA

Consumes 2 phosphate bonds =1 ATP

Where are the 3 locations FAs ca be oxidized and how they differ?

Mitochondria —>beta oxidation

• long (14-20), medium (6-12) and short chain (<6)

Peroxisomes —→ beta oxidiaiton

• very long chain >20 and branched chains (hardest to break down in theory)

Smooth ER

• w oxidiaiton for FA —> dicarboxylic acids (minor pathway unless beta oxidiaiton is not working ***)

How are long chain FAs >12 transported? What about medium chain FAs?

Long chain FA transport will depend on carnitine

CPTI is the rate limiting step (differnt isoforms in different tissues)

• fatty acyl CoA +caratine —> fatty acyl caratine +CoA

CAT shuttles it into the matrix via antiport of caratine and CA caratine

CPTII transfers back to fatty acyl CoA —>beta oxidiaiton

**medium chain FAs do not need this

Describe caratine location, properties, and origins

Location: starts in skeletal and finished in the liver and kidney

Prop: Bound to lysine and req S adenosine methionine (SAM) as a methyl donor

Transported cia caratine transported

Used a dietary supp to accelerate FA oxidiaiton

What happens to patient B when they no longer produce carnitine? How does this relate to the liver, heart, and skeletal muscles?

If they can no longer produce carnitine, they will then have a accusation of long chain FAs int he liver heart and skeletal muscles

This is due to them not being able to leave the liver and be transferred to ketones

FAs will still exist in the short chain form to be able to supply the heart and skeletal muscle shower the brain will be left without energy

Clinical relevance: Ibality to degrade long chain FAs —→ hypoketoic hypoglycemia as no ketone and glucose is present. Gluconeogneeis also impaired in liver.

Labs: Elevated liver enzyme and ammonia

Treatment: high carb, low fat diets with only medium chain FAs

A pateint has low plasma acyl caratine, low plasma free caratine, and evaluated urine free caratine. What type of deficiency are we seeing here?

Primary carnitine deficency (into the cell)

A pateint has low plasma acyl caratine, high plasma free caratine, and normal urine free caratine. What type of deficiency are we seeing here?

CPTIA deficiency (liver)

A pateint has high plasma acyl caratine, low plasma free caratine, and normal urine free caratine. What type of deficiency are we seeing here?

CAT deficency

A patent has high plasma acyl caratine, low plasma free caratine, and normal urine free caratine. What type of deficiency are we seeing here?

CPTII deficiency

Describe the net in and outs of beta oxidiaiton after one turn

Occurs int he mitochondrial matrix

Beta carbon is oxidized

Decreases by 2 carbons every cycle

FADH2, NADH, acetyl CoA is generated per turn, + 1 ATP

Acetyl Coa—>TCA and —>ketone body synthesis in the liver.

Proceeds until cis bond is reached —> isomerized to trans then can proceed further

Oxidiaiton of odd chain fatty acids differs how?

We will have 1 acetyl Coa and 1 propionate CoA (3 carbon) int he last cycle

• degraded to succinylcholine Coa —>TCA

***If deficiency in the propanol Coa degregation —> organic academia(propionate or methlymalonic acidemia)

Oxidiaiton of medium chain FAs differ how?

They do not need to be converted to fatty acyl Coa or carnitine to enter the mito

Not stored as triglycerides

Peroxisomes breaks long to medium then transports via carnitine

Medium chain acyclovir Coa dehydrogenase deficency (MCAD)

Causes hypoketoic hypoglycemia

• increased C6-10 acylcarntintin, dicarboxylic acids (w oxi)nad inhibition of gluconeogensis

Treatment: Glucose and carbs rich diet, acid fasting, uncooked startch at bedtime to supply brain with energy source in case of fasting state activation.

What are two disease associated with abnormal ketone body levels?

Hypoketoic: If deficency in either carnitine meta or B oxi (MCAD) —>hypoketoic hypoglycemia

Ketoacidosis: T1DM ie lactate of insulin goes into fasting state

Acute compensation for alcohol consumption : Increased NADH caused inh of TCA cycle. Acetyl Coa then used for ketone body synthesis

Describe the regulation of B oxidiaiton

Describe the properties of w oxidiaiton and why it is used?

Takes place int he smooth ER

Produces dicarboxylic acids —> mito beta oxidiaiton

Used if B oxidation is to a viable ie MCAD

When are peroxisomes used? What i te main difference?

Very long chains ie > 22 Or branched

Important for the NS

Does not need carnatine as they come to the perixisome in their conjugated form of CoA

Starts at the alpha and NOT beta position

• Main difference = no FADH2 produced instead spits out H2O2

A patient comes in elevated levels of long chain and branched FAs int he circulation what is wrong and what disease are link to this deficiency?

Peroxisomal defificeneies - causes NS disorders as they are important int he NS

Diseases: Classic refuse disease, c linked adrenoleukodystrophy, perosisome biogen disorders (Zellwger syndrome spectrum)