Liver Metabolism 3: Lipid Metabolism Flashcards
What is the break down of dietary lipids?
90% of all lipids are fats and oils
- triglycerides and TAGs
10% is cholesterol, phospholipids, etc.
Products of all lipid digestion’s is the following:
- glycerol back bone
- medium and short chain FAs
- chylomicrons (contain TAGs, cholesterol, and phospholipids)
How are medium chain Fatty acids broken down from the blood?
1) bound to albumin in the blood and taken near hepatocytes
2) released from albumin and bound to fatty acid binding proteins found in hepatocytes and brought to the mitochondria of the hepatocytes
3) are then broken down to acetyl-CoA via B-oxidation within the mitochondria and used in TCA and ETC to generate ATP
How are chylomicron remnants broken down in the blood?
1) transferred to hepatocytes via blood stream (aren’t bound to anything)
2) recognized by chylomicron specific receptors on hepatocytes and undergo endocytosis into hepatocytes
3) are degraded via lysosomes in hepatocytes and produces fatty acid CoA and cholesterol groups
3) fatty acyl-CoA uses caratine shuttle system in mitochondria of hepatocytes to get B-oxidase into acetyl CoA
4) cholesterol is not broken down and stored
Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency
Most common inborn error of B-oxidation (1:14000)
Is an autosomal recessive disorder recessive disorder which results in the decreased level of medium chain fatty acid dehydrogenase enzymes which ultimately causes decreased B-oxidation of medium chained fatty acids (6-10 carbon chains) in mitochondria of hepatocytes.
Symptoms:
- severe hypoglycemia (tissues cant use fatty acids as energy so they overuse glucose)
- hypoketonemia
Treatment: avoid fasting and eating foods with high excess of medium chained FAs (dairy, coconut oil, other oils)
What are the differences between Medium chained fatty acids and long chained fatty acids as it pertains to metabolism?
Medium (6-12 carbons)
- found in dairy and oil sources
- binds to albumin and does not get incorporated into Chylomicrons
- liver is primary metabolism site
- enters via facilitated diffusion (doesnt need transporters)
- undergoes B-oxidation and activation in hepatocyte mitochondria
- ultimately forms acetyl-CoA
Long (16+ carbons)
- main ones are palmitate, stearate, oleate, and linoleate acids
- can be either bound to chylomicrons or to albumin
- primary site of metabolism is liver
- activated in cytosol and enter the mitochondria via CPT-1/2 receptor transports
- undergo B-oxidation in the mitochondria and produce a lot of acetyl CoA
How does very long chain (Carbon # greater than 21) FA metabolism work?
most are produced endogenously and are not found exogenously
Travel in blood and plasma via lipoproteins
Are broken down exclusively in liver peroxisomes via B-oxidation
remnants of this break down then enter mitochondria via CPT-1/2 receptors and under go further B-oxidation to produce acetyl-CoA
CPT-1 deficiency
Extremely rare deficiency of the CPT-1 receptor in hepatocyte mitochondria
- inability to use LCFAs for fuel and greatly impairs cellular ability to synthesize glucose during fasting
Symptoms:
- hypoketotic hypoglycemia
- hepatomegaly
- liver malfunction and elevated carnitine in blood
- chronic without treatment = liver failure/seizures/coma/death
- *often gets triggered by periods of fasting or in chronic viral infections**
Zellweger spectrum disorders (ZSD)
Mutations in at least 12 genes of encoding peroxins
- has dysfunctional peroxisomes and inability to metabolize VLCFAs which accumulate in blood
What are the most common end groups of odd number FAs?
Propionyl-CoA and acetyl CoA
- both are seen in odd fatty acid degradation as products
even number fatty acids get degraded completely to acetyl CoA (No propionyl CoA)
Vitamin B12 deficiency often shows what in the urine?
High levels of propionate and methylmalonate
- coenzyme B12 are need to break down these intermediates in proplonyl-CoA metabolism
Heritable methylmalonic acidemia and aciduira
Deficiency in mutase enzymes or the inability of mutase enzymes to use coenzymes for function
- both results in inability to convert Vit. B12 to coenzyme forms
Symptoms:
- neurological defects
- metabolic acidosis
What are the two enzymes required to break down propionyl CoA?
1) Propionyl-CoA carboxylase
- converts propionyl CoA -> D-Methylmalonyl CoA
- requires biotin
2) methylmalonyl-CoA mutase
- converts L-methylmalonyl-CoA -> succinylcholine-CoA
- requires coenzyme B12
What happens in hepatocytes when fatty-acyl-CoA builds up in excess?
Combines with glycerol to form TAG’s
- used to form phospholipids and sphingolipids
- must have glycerol present! (Uses glycerol kinase to attach phosphate groups to the glycerol backbone in liver or glycerol 3-phosphate dehydrogenase in adipose tissue)
Can also combine with phospholipids into VLDL molecules as well if needed
What is the most common membrane bound lipid?
Phosphatidylcholine
- requires phosphaditic acid intermediate molecule from TAG synthesis to make
- *both phospholipids and TAGs require MTP to form VLDL**
- are exported out of liver and sent to peripheral tissues for FA usage as needed
What are the steps of packaging and export of lipids to the systemic circulation
1) liver secretes nascent TAG-rich VLDL particles containing primarily endogenously synthesized lipids or LDL molecules that are endocytosed form the systemic circulation
2) Apo C-2 and apo E proteins are transferred from HDL particles and bind to TAGs to form nascent VLDL molecules
3) extracellular lipoprotein lipase, which is activated by apo C-2 degrades VLDL TAGs as needed
- free fatty acids are sent to tissues as needed
- glycerol is sent to the liver
4) Apo C-2 and E are returned to HDL molecules to form LDL molecules
5) LDL molecules bind to extrahepatic tissues and is endocytosed into liver to start cycle again
