Chemical Pathology - Lipoproteins

Question 1

what are atherosclerotic plaques formed of?

Answer 1

• necrotic core (dead macrophages) of cholesterol crystals
• surrounded by foam cells (macrophages)
• topped with fibrous cap

Question 2

what are the difference plasma lipoproteins?

Answer 2

• chylomicron (high TGs)
• VLDL (high TGs)
• LDL
• HDL

Question 3

describe the transport of cholestrol

Answer 3

• cholesterol enters intestines
• solubilised into mixed micelles
• cholesterol transported across intestinal epithelium by NPC1L1 (main determinant of transport)
• 2 transporters can transport cholesterol back into lumen of intestines (ABC G5, ABC G8)
• balance between these 2 transporters determines net amount of cholesterol absorbed
• bile acids resorbed in terminal ileum
• cholesterol downregulates activity of HMG CoA reductase at liver

Question 4

what does HMG CoA reductase do?

Answer 4

enzyme to create acetate and mevalonic acid

i.e. amount of cholesterol synthesised in liver is dependent on amount of cholesterol absorbed in small intestines

Question 5

what are the fates of the cholesterol brought to the liver?

Answer 5

• hydroxylation by CYP7A1 enzyme (7a-hydroxylase) –> bile acids –> excreted via bile ducts
• esterified by ACAT –> cholesterol esters and combined with TG and apoB into VLDL (precursor to LDL)

Question 6

what happens to LDL after circulation?

Answer 6

LDLs bind to LDL receptor on liver

Question 7

what are HDLs responsible for?

Answer 7

picking up excess cholesterol from periphery

ABC A1 transporter packages free cholesterol from periphery into HDLs

Question 8

what does CETP (Cholesterol Ester Transfer Protein) do?

Answer 8

mediates movement of:

• cholesterol from HDL to VLDL
• TGs from VLDL to HDL
• some of HDLs will be taken up by liver via SR-B1 receptor

Question 9

what are the types of primary hypercholesterolaemia?

Answer 9

• Familial hypercholesterolaemia (mutation LDL-R, apopB, PCSK9)
• Polygenic hypercholesterolaemia (NPC1L1, HMG-CoA reductase, CYP7A1 polymorphisms)
• Familial hyper-alpha-lipoproteinaemia (CETP def)
• phytosterolaemia (ABC G5 and G8 mutations –> premature atherosclerosis)

Question 10

what is the pathophysiology of hypercholesterolaemia?

Answer 10

LDL binds to LDL-R and undergoes endocytosis

Question 11

what are the signs and symptoms in homozygotes and heterozygotes?

Answer 11

Homo: corneal arcus, atheroma of aortic arch
Het: corneal arcus, xanthomas

Question 12

what is the function of PCSK9?

Answer 12

bind to LDL-R and aid degradation

Question 13

what is the cause of of familial T-1 hypertriglyceridaemia?

Answer 13

lipoprotein lipase or apoCII def
= less breakdown of CMs
some xanthomas

Question 14

what is the cause of of familial T-IV hypertriglyceridaemia?

Answer 14

increased synthesis of TG (unknown cause)

majority VLDLs

Question 15

what is the cause of of familial T-V hypertriglyceridaemia?

Answer 15

apoA V deficiency

majority VLDLs

Question 16

what are the types of mixed hyperlipidaemia (primary)?

Answer 16

• familial combined hyperlipidaemia (unknown cause)
• familial hepatic lipase deficiency
• familial dys-beta-lipoproteinaemia (ApoE2 polymorphism)

Question 17

what is secondary hyperlipidaemia?

Answer 17

non genetic cause

e.g. PBC

Question 18

what are the causes of hypolipidaemia?

Answer 18

• AB-lipoproteinaemia: MTP def, RARE
• hypoB-lipoproteinaemia: truncatsed apoB
• Tangier disease: orange tonsils, HDL def
• Hypoa-lipoproteinaemia

Question 19

what are the novel lipid-regulating drugs?

Answer 19

• MTP inhibitor (Lopitapide)
• Anti-PCSK9 monoclonal antibody (REGN727)
• Anti-sense apoB oligonucleotide (mipomersen)
• Apolipoprotein A1 infusion therapy (HDL based therapy)
• CETP inhibitor (HDL based therapy)

Question 20

what are the different treatment options for obesity?

Answer 20

• low calorie diet and exercise
• iatrogenic metabolism (e.g. orlistat)
• bariatric surgery: BMI > 40 (e.g. gastric banding, bypass, biliopancreatic bypass)