10Cardio Flashcards
What are some of the other single gene defects which can alter cholesterol metabolism and causing atherosclerosis?
Bile acid formation disorder, Cholesterol Ester Storage Disorder and Tangier Disease
What are the common features of these other rarer single gene defect disorders?
Common features:
All conditions are rare (population phenotype frequency 1/106 to 1/107
All proteins affected are catalytic and inheritance is autosomal recessive
Mutations reduce activity of proteins
What is affected in Bile Acid Formation disorder and what are the consequences?
Cholesterol 7alpha-hydroxylase; this affects the rate limiting step for bile acid synthesis from cholesterol. Cholesterol accumulation in the liver and reduced LDLR activity.
What is affected in Cholesterol Ester Storage disorder and what are the consequences?
Lysosomal acid lipase; this affects LDL-derived cholesteryl ester hydrolysis to cholesterol in lysosomes. Cholesteryl ester accumulation in extra-hepatic cells - foam cell formation.
What is affected in Tangier disease and what are the consequences?
ABCA1; this affects cholesterol transfer from cells to apoAI-rich pre-beta1-HDL. Failure to clear cholesterol from extra-hepatic cells = foam cells.
How is cholesterol 7alpha-hydroxylase involved in bile acid synthesis?
Cholesterol 7α-Hydroxylase (CYP7A1)
Is a haemoprotein which binds O2 and NADPH
Truncated protein lacks the haem binding domain
Mutation does not abolish ALL bile acid synthesis due to existence of acidic pathway. But does indicate the importance of the neutral (CYP7A1) pathway in the synthesis of bile acids
Increased liver cholesterol caused by reduced synthesis of LDLR
How is the ABCA1 protein linked to cholesterol efflux and Tangier’s disease?
ABCA1 = a member of the ATP Binding Cassette family of membrane proteins
Found at the plasma membrane
2 transmembrane and 2 nucleotide binding domains
Highly hydrophobic regulatory domain
ABCA1 gene mutations impair apoA1-mediated efflux from the cells of free cholesterol (FC) and phospholipid
What is the ABCA1 lipid secretory pathway?
ABCA1 gene mutations impair apoA1-mediated efflux from the cells of free cholesterol (FC) and phospholipid
Accumulation of cholesteryl ester in non-hepatic tissue
Foam cell formation
Reduced plasma HDL
Orange tonsils
How is the balance between LDL uptake and HDL efflux affected in patient’s with Tangier’s disease?
In Tangier’s disease, homozygotes show no or very low plasma HDL.
HDL efflux shows and so increases cholesterol accumulation in macrophages - foam cells.
Associated with premature intimal thickening of arteries - 6x normal incidence of cardiovascular disease.
What happens in cholesterol ester storage disorder (CESD)?
Lysosomal acid lipase affected
In CESD, cholesterol esters are not broken down to cholesterol
Cholesterol esters accumulate secondary lysosome - extrahepatic tissue - formation of foam cells
What happens in non-inherited “Population Hypercholesterolaemias”?
Inherited conditions (eg types II and III, single gene disorders) account for less than 10% of the incidence of hypercholesterolaemia in the population Resembles symptoms of FH in heterozygotes but is less severe = takes more than 40 years to develop = caused by decreased activity/levels of LDLR Diet, smoking, diabetes/obesity, environmental factors etc. account for remainder
How does the liver LDL receptor respond to a high fat diet in normal individuals?
Increased delivery of chylomicron remnants (containing CE) via LRP
Increased liver cholesterol concentration which inhibits formation of mature SREBP-2
Reduced transcription of LDL receptor gene, resulting in lower LDL receptor expression causing:
Increased formation of LDL and decreased hepatic clearance of plasma LDL
High fat may also increase the synthesis of VLDL (due to effect on MTP)
What is the link between dietary fat and cholesterol and blood cholesterol levels?
Both dietary fat and dietary cholesterol raise blood cholesterol Fat is more effective than cholesterol, but the type of fatty acid in triglyceride is critical Saturated fats (C12-16 but not C18) and trans fatty acids (TFA) cause increase plasma cholesterol Unsaturated fats (cis) do not increase cholesterol
How do saturated fats lead to raised LDL concentrations in the blood?
From hamster feeding studies:
These saturated fats:
Repress LDL receptor mRNA = less LDLR protein = higher plasma LDL/IDL
Increase MTP mRNA = higher VLDL secretion = higher plasma IDL/LDL
Increase fatty acid biosynthesis = higher VLDL secretion = higher plasma IDL/LDL
Mechanism?
Transcriptional control:
PPAR (ligands), SREBPs, LXR, HNF4
High LDL:HDL ratio = at risk of developing atherosclerosis
What are the effects of unsaturated fats on serum cholesterol levels?
Unsaturated fats (MUFA/PUFA) Increase LDL receptor mRNA = more LDLR protein = lower plasma LDL/IDL Increase fatty acid oxidation = lower VLDL secretion = lower plasma LDL/IDL Decrease fatty acid biosynthesis = lower VLDL secretion = lower plasma LDL/IDL Mechanism? Transcriptional control: PPAR (ligands), SREBPs, LXR, HNF4 Low LDL:HDL ratio = reduced risk of developing atherosclerosis
