Lipid Metabolism, Dyslipidemias and Treatment 3

Question 1

Adipose tissue, especially adipose cells around visceral organs can contribute negatively to CV health, name some of its adverse endocrine effects.

Answer 1

increase insulin resistance (increased glucose)
increased leptin (increased appetite)
increased SNS (HTN)
increased angiotensin (HTN)
increased inflammatory mediators
increased FAs (increased atherosclerosis)

** esp. important as adipose cells get larger

Question 2

How does insulin resistance contribute to dyslipidemia?

Answer 2

in insulin resistance, HSL is not inhibited and FFAs and glycerol are shuttled to the liver via VLDL, leading to greater numbers of VLDL in circulation

Question 3

6. List 3 drugs that function to raise HDL and to lower TG.

Answer 3

niacin (also lowers LDL-C)
fibrates
omega-3-fatty acids

note that alcohol and estrogens can uncouple the relationship between HDL and TG

Question 4

6. What are the effects niacin (B3) on cholesterol synthesis?

Answer 4

niacin B3 reduces VLDL production (reduces TG and then also less LDL, at high doses) and blocks catabolism of HDL

modest evidence for CVD reduction; long-term safety

Question 5

6. Name 3 mechanism for the action of niacin to reduce.

Answer 5

1. reduces lipolysis from adipocytes
2. reduces diaclyglycerol acyltransferase (responsible for VLDL synthesis)
3. reduces apo A-1 catabolism, while permitting removal of cholesterol from HDL

Question 6

6. Why aren’t all patients on niacin given its efficacy and safety?

Answer 6

major side effects:
flushing and itching (reduced with aspirin)
abdominal pain, ulcers
hyperglycemia (contraind. with DM2)
hepatotoxicity (contraind. with liver disease)
gout
myalgia/myopathy esp with statins (esp among Asians)

contraind. with pregnancy

Question 7

6. What are the major actions of fibrates on lipid metabolism?

Answer 7

decrease VLDL production
increase lipolysis of VLDL and IDL

end result is reduced TG, increased HDL_C [maybe decrease in LDL-C, depending on TG]

Question 8

What is the mechanism of action for fibrates?

Answer 8

activation of PPAR-a synth of apo A-I and A-II
activation of LPL and reduces apo CIII (LPL inhibitor)
stimulates hepatic FA uptake and B-oxdaiton (reduces TG syn)

Question 9

6. What adverse effects should you consider when using fibrates?

Answer 9

stomach aches are pretty common
concentration of bile pool can lead to call stones
phenylfibrate is best with statins, lower risk of myalgia/myopathy
possibly blocks active secretion of creatine

contraindications: liver disease, sever kidney disease, pregnancy

Question 10

6. How do omega-3-fatty acid’s effect lipid levels?

Answer 10

reduces TG (20-50%)
modest effects on HDL-C related to TG reduction
LDL-C may increase or not change

Question 11

6. Discuss the mechanism and safety of omega-3 FA.

Answer 11

complex mechanism: inhibits DGAT, reduces lipolysis, stimulates hepatic fatty acid catabolism by B oxidation (less TG)

long history of safety with adverse effects including eructation, flatulence, abdominal pain and bruising/bleeding

Question 12

Broadly speaking describe the process of deciding on lipid medications.

Answer 12

1. estimate the 10 yr risk to the patient of developing CVD
2. intensity of therapy is adjusted to patient’s risk of CVD, currently recommendations have gotten away from using hard numerical guidelines

Question 13

What is the most severe risk to those patients with TG over 500mg/dL.

Answer 13

high risk of pancreatitis

Question 14

6. What is the first line treatment of patients with dysilipidemia and TG<500mg/dL

Answer 14

STATINS! and more statins!

note with increasing TG, it can be helpful to add niacin as a secondary treatment

Question 15

Which disease of dyslipidemia is known to cause xanthomata?

Answer 15

familial hypercholesteroliema (fatty deposits in the tendons)

Question 16

Which enzymes are directly involved in the formation of small, dense LDL particles?

Answer 16

cholesterol ester transfer protein (CETP)

hepatic tryglyceride lipase (HTGL)