Dislipidemias/Bile salts/Drugs

Question 1

Bile Salts

Answer 1

Glycocholic acid and taurochenodeoxycholic acid (added glycine to cholic acid and taurine to chenodeoxycholic acid)

Question 2

secondary bile acids

Answer 2

Deoxycholic acid and lithocholic acid (first the bile salts are deconjugated to primary bile acids and then deconjugated to these secondary bile acids)

Question 3

Primary Bile Acids

Answer 3

Cholic Acid and Chenodeoxycholic acid

are first made in the liver, or can then be deconjugated from bile salts by colonic bacteria

Question 4

HMG-CoA Reductase Inhibitors

Answer 4

AKA Statins (Lovastatin, Simvastatin)
are structural analogs of HMG‐CoA that are reversible, competitive inhibitors
Decreased de novo cholesterol synthesis
-Decreased [cholesterol]cyto
-Increased LDL‐receptor synthesis
-Increased LDL receptor‐mediated endocytosis
-Decreased serum LDL‐C

Question 5

Bile Acid Sequestrants (Resins)

Answer 5

Cholestyramine is a (+)‐charged resin which forms ionic bonds with bile acids. This insoluble complex in the intestine is then excreted in the feces. This reduces the reabsorption of bile acids/salts; i.e. more bile acids/salts are excreted (>5%) and less are re‐absorbed.
When more bile acids are excreted, de novo synthesis increases using cholesterol as its substrate to make up the difference
-Decreased [cholesterol]cyto
-(i) Increased LDL‐receptor synthesis &
(ii) increased HMG‐CoA reductase
-Increased LDL receptor‐mediated
endocytosis
-Decreased serum LDL‐C

Question 6

Cholesterol absorption inhibitors

Answer 6

Ezetimibe binds to a protein crucial for cholesterol absorption located on the GI tract epithelium as well as hepatocytes. This binding prevents cholesterol absorption.
Decreased intestinal cholesterol absorption:
-Decreased [cholesterol]cyto
-(i) Increased LDL‐receptor synthesis &
(ii) increased HMG‐CoA reductase
-Increased LDL receptor‐mediated
endocytosis
-Decreased serum LDL‐C

Question 7

To maximize the serum cholesterol lowering effects

Answer 7

combination therapy (either Statins/Ezetimibe or Statins/Cholestyramine combo therapy) is typically used to minimize the increased de novo cholesterol synthesis.
• Mediated through an increase in LDL receptor expression
• Increased LDL‐receptor mediated endocyosis
• Reduced serum LDL‐C levels

Question 8

Familial Hypercholesteremia (type IIa hyperlipidemia)

Answer 8

cause: a deficiency in LDL receptor
A defective LDL receptor disrupted serum LDL
endocytosis
-Serum LDL increases
Due to a decrease in endocytosed LDL, cytosolic cholesterolb decreases which leads toban increase in HMG‐CoA reductase synthesis, i.e. an increase in de novo synthesis.

Question 9

Niacin

Answer 9

inhibits lipolysis = a decrease in VLDL and LDL production (serum TAGs lowered)
also decreases Apo-AI breakdown, extending HDL’s half-life (increasing HDL)

Question 10

Fibrate

Answer 10

• activates LPL -> an increase in VLDL clearance
• decreases nascent VLDL secretion (serum TAGs lowered)
• Fibrate also increases Apo A-I gene expression, increasing HDL production to increase HDL

Question 11

cholelithiasis

Answer 11

cholesterol gallstone disease
thee factors needed for development of cholesterol gallstone
-increase in cholesterol secretion into the bile (can be caused by obesity, the metabolic syndrome, high caloric & cholesterol rich diets, increased HMG-reductase or rapid weight loss in obese individuals
and/or decreased levels of bile salts of phospholipids or delayed/incomplete gallbladder emptying and bile stasis.

Question 12

Abetalipoproteinemia (CM Retention Disease)

Answer 12

Cause: loss of function mutation on MTP gene
this means that TAGs are not transferred to nascent CM and nascent VLDLs, result these cannot be assembled in hepatocytes.
Lipid profile: CM, VLDL and LDL are almost absent from plasma, resulting in hyopolipidemia
dietary fats accumulate in enterocyte and failure to thrive. generalized weakness and skeletal deformations
Therarpy: low-fat, calorie rich diet with high dose vitamin suppliments

Question 13

Familial Chylomicronemia (Type I Hyperlipidemia)

Answer 13

Cause: a deficiency of LPL or a deficiency of Apo C‐II
TAG in the CM cannot be hydrolyzed. Thus, CM remains to be TAG‐rich.
lipid profile: Elevated fasting CM (high TAG).
o The serum appears turbid and milky;
after centrifugation, the creamy top layer is observed. Cholesterol levels are
normal. Note: it is unclear why VLDL is not elevated as a result of LPL or Apo CII deficiency.

Question 14

Polymorphism of Apo E gene; Apo E-variant binds poorly to Apo E receptor

Answer 14

Familial dysbetalipoproteinemia
decrease in clearing of IDL and CM remnants
Elevated IDL and CM remnants
That is, serum TAGs and Cholesterol are both elevated