Chemical Pathology - Lipoprotein metabolism, CVD and obesity Flashcards
What is the role of HDL?
Picks up excess cholesterol from the periphery and transports it to liver
What is the role of the enzyme CETP in cholesterol metabolism?
movement of cholesterol from HDL to VLDL conversion
movement of triglyceride from VLDL to HDL
What is the key enzyme involved in cholesterol synthesis?
HMG CoA reductase
rate determining step that converts HMG Coa to mevalonate in the synthesis of cholesterol
Which enzyme converts cholesterol to cholesteryl ester?
ACAT
Acyl-coenzyme A:cholesterol acyltransferases
What is VLDL constituted of?
ApolipoproteinB, cholesteryl ester and triglyceride
What is the function of 7-alpha hydroxase in cholesterol metabolism?
Converts cholesterol to bile acids
What is the main component of mixed micelles?
Bile acids
Where are bile acids resorbed?
Terminal ileum
What controls the amount of cholesterol resorbed into the intestine?
Balance of 2 transporters : NPC1L1 and ABC G5/G8
NPC1L1 mediates intestinal cholesterol absorption and it may also limit hepatobiliary cholesterol excretion,
responsible for biliary and transintestinal secretion of cholesterol and dietary sterols.
What is the inheritance pattern of familial hypercholesterolaemia type II?
dominant
What name is given to an inherited predeliction to high HDL, and what mutation causes this?
Familial hyperalphalipoproteinaemia
= CETP deficiency
Cholesteryl ester transfer protein
What condition is caused by ABC G5/G8 mutation?
Phytosterolaemia
What is phytosterolaemia?
AR Inherited condition that allows plant sterols to enter the plasma freely, which are more athrogenic than cholesterol itself causing premature atherosclerosis
Recall 3 clinical signs of hypercholesterolaemia
Xanthalasma
Arcus
Tendon xanthoma
How can you examine for tendon xanthoma?
Feel back of ACL
What are the different types of primary hypertriglyceridaemia? what’s the inheritance
I, IV and V
all dominant
characterized by the liver overproducing very-low-density lipoproteins (VLDL
What is A-beta-lipoproteinaemia?
MTP deficiency causing hypolipidaemia
Inability to absorb fat results in deficiencies of lipids and various essential vitamins
Recall 4 inherited conditions that can cause hypolipidaemia
A-beta-lipoproteinaemia - AR
Hypo-beta-lipoproteinaemia - AD
Tangier disease (HDL deficiency)
hypo-alpha-Lipoproteinaemia
What is the effect of statins on cholesterol levels?
Very effective at reducing LDL, also reduce triglyceride and HDL
What is the effect of fibrate drugs on cholesterol levels?
Very effective at reducing triglycerides,
e.g fenofibrate
also reduces LDL
What is the role of PCSK9?
Binds LDLR and promotes its degradation
What is the mechanism of action of statins?
HMG coA reductase inhibition
What is the most potent pharmacological agent at reducing low density lipoprotein concentration in blood?
evolocumab - pcsk9 inhibitor
another pcsk9 inhibitor is alirocumab
what enzyme converts cholesterol in liver to bile acids
7a hydroxylase
what packages cholesterol esters
Microsomal triglyceride transfer protein (MTP)
what packages free cholesterol from periphery into HDLs
ABC A1
give 4 types of primary hypercholesterolaemia
Familial hypercholesterolaemia (FH)
Polygenic hypercholesterolaemia
Familial hyper-a-lipoproteinaemia
phytosterolaemia
give 3 mutations seen in FH
LDL-R
apoB
PCSK9
result of a loss vs gain mutation in pcsk9
Gain-of-function mutations in PCSK9 have been associated to hypercholesterolemia and to an increase in cardiovascular risk. = FH!
In contrast, loss-of-function mutations in PCSK9 result in low LDL-c levels and seem to decrease the risk of coronary heart disease, without having any known negative impact on human health
what 2 proteins in implicated in familial type 1 hypertriglyceridaemia
apoC 2 deficiency or lipoprotein lipase def (elevated chylomicrons)
what gene in implicated in type 5 hypertriglyceridaemia
apoA-V deficiency
what is mixed hyperlipadaemia, give an example of a disease
characterised by raised triglyceride AND cholesterol levels
familial dysbetalipoproteinemia
type 3 hyperlipoproteinameia aka
what polymorphism in type 3 Hyperlipoproteinemia/familial dysbetalipo
Apoe2
(Apoe4 increases Alzheimers, ApoE2 decreases it)
wat 2 signs are diagnostic of dysbetalipoproteinemia/type 3 Hyperlipoproteinemia
Yellow infiltration of the palmar creases
xanthoma on the elbows.
what mutation in hypoalphalipoproteinaemia and hypobetalipoproteinaemia
hypo alpha = apoA-I mutations
hypo beta = truncated apoB
mutation in ABC A1 causes
tangier disease
mutation causes HDL def
Tangier disease is most often characterized by
enlarged orange- or yellow-colored tonsils. This discoloration is due to fatty deposits accumulating in the tonsils
state a MTP inhibitor
lomitapide
give an antiPCSK9 monoclonal antibody
REGN727 aka Alirocumab
give a drug that inhibits inhibits apolipoprotein B 100 (apoB) protein synthesis
mipomersen
risk of liver damage
give 3 drugs to treat FH
hetero - statins
homo - mipomersen, lomitapide
give a CVD risk marker
lipoprotein a an ldl
what drug to manage high lipoprotein a
nicotinic acid aka niacin
It is unique among the various lipid therapies in that it can not only reduce all of atherogenic lipid fractions (total cholesterol, low-density lipoprotein, very low-density lipoprotein, non-HDL lipoproteins, and triglycerides), but is also the most effective agent for raising high-density lipoprotein (specifically Apolipoprotein A-1). It is also the only lipid therapy that can lower lipoprotein (a).
give 2 surgeries for obesity, which is better
billiopancreatic diversion > gastric bypass
(both better than medical therapy)
ezetimibe targets what
NPC 1L1
