From molecules to cells lecture 8: Chylomicron retention diseases and familial hypercholaemia

Where does chylomicron biosynthesis occur? (2 answers)

a) Nucleus

b) Golgi apparatus

c) Endoplasmic reticulum (ER)

d) Mitochondria

b and c

What is the function of prechylomicrons in chylomicron biosynthesis?

a) They transport dietary lipids through the bloodstream.

b) They carry proteins to the small intestine.

c) They act as enzymes for lipid digestion.

d) They are precursors that assemble in the ER for chylomicron formation.

d

In Chylomicron Retention Disease (CRD), what is the primary defect?

a) Apoprotein misfolding in the ER

b) Defective export of prechylomicrons from the ER

c) Defective assembly of prechylomicrons

d) Excessive chylomicron exocytosis

b

What is the role of Sar1 in chylomicron biosynthesis?

a) Initiating assembly of COPII coat proteins on Golgi membranes, which promotes export of prechylomicrons to the ER

b) Mediating the fusion of prechylomicrons with transport vesicles

c) Initiating assembly of COPII coat proteins on the ER membrane, which promotes export of prechylomicrons to the golgi

d) Inhibiting the formation of chylomicrons in the ER

c

How would a drug that inhibits GTP hydrolysis by Sar1 likely affect chylomicron biosynthesis?

a) Increase the formation of COPII coated vesicles at the ER

b) Decrease the formation of COPII coated vesicles at the ER

c) Prevent the assembly of chylomicrons in the Golgi

d) Enhance the breakdown of chylomicrons in the cytosol

a

How do mutations in Sar1b affect chylomicron biosynthesis?

a) Enhance the export of prechylomicrons from the ER

b) Prevent the formation of COPII coated vesicles at the ER

c) Disrupt the export of prechylomicrons from the ER

d) Increase the stability of prechylomicrons in the Golgi

c

What is the role of Sar1-GEF (exchange factor) in the process of COPII activation?

a) It binds to COPII coat proteins and triggers their assembly on the Golgi membrane.

b) It binds to Sar1 and promotes the exchange of GDP for GTP, activating Sar1.

c) It directly initiates the formation of COPII-coated vesicles on the ER membrane.

d) It facilitates the fusion of COPII vesicles with the target membrane.

b

Which of the following is NOT a symptom of Chylomicron Retention Disease (CRD)?

a) Slow growth

b) Weight gain

c) Gastrointestinal effects

d) Eyesight problems

d

What is the primary defect associated with Familial Hypercholesterolaemia (FH)?

a) Impaired cholesterol synthesis in the liver

b) Mutated HDL receptors, leading to impaired cholesterol uptake

c) Dysfunctional LDL receptors leading to impaired cholesterol uptake

d) Enhanced cholesterol transport to peripheral tissues

c

Which class of mutations in LDL receptors is characterised by the prevention of proper folding, leading to ER retention and degradation?

a) Class 1 mutations

b) Class 2 mutations

c) Class 3 mutations

d) Class 4 mutations

b

What is the consequence of class 4 mutations in LDL receptors in Familial Hypercholesterolaemia (FH)?

a) Decreased binding of LDL to the receptor

b) Enhanced internalisation of LDL receptor-LDL complex

c) Impaired biosynthesis of the LDL receptor

d) LDL binds to the receptor as normal, but the complex is not internalised

d

What is the primary mode of action of statins in treating Familial Hypercholesterolaemia (FH)?

a) Enhancing LDL receptor expression

b) Inhibiting dietary cholesterol absorption

c) Stimulating cholesterol synthesis in the liver

d) Blocking the action of cholesterol transport proteins

a

What is the inheritance pattern of Familial Hypercholesterolaemia (FH)?

a) Autosomal recessive

b) Autosomal dominant

c) X-linked recessive

d) Mitochondrial

b

Which mutation in LDL receptors is associated with the prevention of binding to LDL particles in Familial Hypercholesterolaemia (FH)?

a) Class 1 mutations

b) Class 2 mutations

c) Class 3 mutations

d) Class 4 mutations

c

What is the consequence of mutations in the cargo adapters for cholesterol?

a) Enhanced cholesterol metabolism

b) Increased expression of LDL receptors

c) Autosomal dominant hypercholesterolaemia

d) Autosomal recessive hypercholesterolaemia

d

Which medication inhibits HMG-CoA reductase, thereby increasing the expression of LDL receptors?

a) Statins

b) Ezetimibe

c) Fibrates

d) Bile acid sequestrants

a

What is the primary cause of lysosomal storage diseases?

a) Defects in mitochondrial function

b) Mutations in lysosomal acid hydrolases and transporters

c) Dysregulation of endoplasmic reticulum (ER) function

d) Impairment of nuclear membrane integrity

b

Which disease is caused by mutations in the lysosomal acid beta-glucosidase?

a) Niemann-Pick type C

b) Gaucher disease

c) Tay-Sachs disease

d) Fabry disease

b

What is the molecular basis of Gaucher disease?

a) Accumulation of phospholipids in the lysosomes

b) Impaired lysosomal acidification

c) Misfolding of lysosomal acid beta-glucosidase, leading to accumulation of glycolipids

d) Defective lysosomal membrane integrity

c

Which treatment strategy involves injecting synthetic enzymes that are taken up by endocytosis?

a) Substrate reduction therapy

b) Gene therapy

c) Enzyme replacement therapy

d) Pharmacological chaperone therapy

c

What is the function of miglustat in the treatment of Gaucher disease?

a) Promotes correct folding of misfolded enzymes

b) Inhibits glucosylceramide synthesis

c) Stimulates lysosomal acidification

d) Enhances lysosomal fusion with autophagosomes

b

Which of the following diseases can be linked to the quality control function of the endoplasmic reticulum that retains misfolded proteins? (3 answers)

a) alpha 1-antitrypsin deficiency

b) Cystic fibrosis

c) Alzheimer's disease

d) Buruli ulcer

e) Familial Hypercholesterolaemia

a, b and e

Two types of mutations located in the signal sequence of [x] are linked to Diabetes. In the one case the mutations perturb the interaction of the precursor protein with the [y] complex in the ER membrane and half of the newly made protein is not translocated. In the second case the protein is correctly translocated across the membrane but it does not [z] correctly inside the ER lumen.

x = insulin

y = Sec61

z = fold

The molecular basis for chylomicron retention disease is:

a) A diet that is very high in trans-unsaturated fatty acids

b) A mutation in Sar1

c) A mutation in Sec24

d) A mutation in Sec61

e) A mutation in the NPC1 protein

b

The aggregation-prone Aβ peptide is produced by proteolytic cleavage of the amyloid precursor protein that occurs after the protein has been internalised and delivered to the _______

endosome