Lecture 7 Flashcards
Cholesterol modification to form bile acids.
Hydroxylation, side chain cleavage, conjugation to glycine or taurine.
What do all steroids have in common?
Cholesterol moiety.
Which cell type must diet-derived lipids enter to be synthesized into macromolecular forms?
Enterocytes.
Where do chylomicrons originate?
Only from the intestine.
Where can excess dietary cholesterol mix in with de novo cholesterol?
In the small intestine.
Dyslipidemias.
Abnormal lipid concentration in the blood. Different types: hypertriglyceridemia, hypercholesterolemia. Can be genetic or acquired.
Abetalipoproteinia: an example of hypocholesteroemia.
B lipoprotein is missing. Low to undetectable levels of circulating chylomicrons due to malabsorption of fat and fat-soluble vitamins. Solution: limit triglyceride intake to medium chains (not long) and less than 15 g per day. Individuals live, but are very sick.
Hypocholesterolemia.
Very low or no chylomicrons, absorption in the intestine is not good, packaging of fats is not good, there can be complete absence of bile acids (though the individual would not survive).
Symptoms of abetalipoproteinemia.
Chromic diarrhea (steatorrhea), rhinitis pigmentosa (because the individual cannot absorb fat-soluble vitamin A, ataxia, star-shaped RBCs (Membranes of phosphatidylcholine are not well made).
Name a lipid metabolizing enzyme.
ACAT.
Lipid carrier proteins.
MTP, Apo 48.
Name a fatty acid transporter.
CD36.
In the absence of ACAT…
You cannot convert cholesterol into cholesteryl esters.
MTP is required for…
Transport of triglycerides and cholesteryl esters between intracellular membranes (it is a carrier protein). It is essential for chylomicron assembly.
Membrane-bound receptors on the surface of enterocytes.
NPC1L1 (cholesterol receptor), FATP4 and CD36 (fatty acid receptors), and MFSD2A (phospholipid receptor).
Ezetimibe.
It can block cholesterol absorption without affecting the absorption of other lipids. Ezetimibe is a competitive inhibitor with cholesterol for the NPC1L1 binding site.
Familial hypercholesterolemia (FH).
Studied using fibroblasts (skin cells); found the molecular mechanism related to cholesterol transport, biosynthesis, etc.
Genetic metabolic disorders.
1 gene can code for many enzymes. Can be inherited: defects in specific genes are passed on to the next generation.
Encode project.
Most of the genome is composed of regulatory elements. The DNA double helix can be packaged into chromatin to shut down transcription; methylation can also affect transcription and translation.
Name on shut-down technique of DNA.
Methylation.
Long-range regulatory elements.
They make instructions to make proteins.
Epigenetic modification.
The entire genetic information is in on chromosome. Access to the information can be hindered by methylation or acetylation of the histones so the DNA cannot sit properly.
Purpose of epigenetic modification.
A mechanism for controlling the use of genetic information during the lifetime of the organism, as well as the next generation. Certain regulatory regions in the parents are marked by the system to be passed on to the next generation; nutrition is a strong regulator of marking the genome. These markings are not permanent.
What influences the marking of the genome in epigenetic modification?
Nutritional status.
Familial Hypercholesterolemia (FH).
Lipoproteins are isolated from the fibroblasts of patients and are purified. The metabolism of cholesterol can be observed: through the use of isotopes.
Clinical features of FH.
High concentration of cholesterol in the blood, fasting plasma is milky due to high lipid content; a normal individual would have yellow fasting plasma. Cholesterol deposits in the skin: xanthelasmas or xanthomas.
What is the usefulness of growing fibroblasts from an FH individual in the lab?
You can subject the cells to different conditions and study their responses.
What can be found in lipoproteins?
Triacylglycerols, apolipoproteins, cholesteryl esters, phospholipids, etc.
Radioactive tracers added to lipoproteins.
H3 or I125 can be added on fatty acyl chains or cholesterol moiety. You can follow the pathway of a specific type of lipoprotein.
Use of radioactive tracers: effect of LDL on metabolism of cholesterol.
We can see how a normal cell binds LDL, whereas an FH cell does not. We can see the FH cells do not have a lot of LDL inside. FH cells do not have much hydrolysis.
Hydrolysis of Apo B results in…
Amino acids.
Hydrolysis of cholesteryl esters results in…
Cholesterol.
Conclusions of FH cells regarding LDL.
FH cells are unable to bind, internalize, or metabolize LDL.
