Lipid Metabolism

Question 1

Explain the role of lipoproteins in atherogenesis.

Answer 1

• Lipoproteins determine the atherogenicity

o By quantity (concentration) → number of LDL particles drives the disease

o By quality (by size) → LDL size modulates the risk Small dense lipoproteins:

o More particles

o Easier access into vessel wall

o Longer circulatory time

o Easily oxidized

o Predicted by low HDL-C and high TG levels

Question 2

Components of CM

Answer 2

Density <0.95

Diameter: 75-300

90-96% TAG

Apoplipoproteins: B-48, E, C-II

Question 3

Components of VLDL

Answer 3

Density: 0.95-1.006

Diameter: 30-80

60% TAG

Apolipoproteins: B-100, E, C-II

Question 4

Components of IDL

Answer 4

Density: 1.006-1.019

Diameter: 23-35

Apolipoproteins: B-48, B-100, E

Question 5

Components of LDL

Answer 5

Density: 1.019-1.063

Diameter: 18-25

50% Cholesterol

Apolipoproteins: B-100

Question 6

Components of HDL

Answer 6

Density: 1.063-1.21

Diameter: 5-12

20% cholesterol

Apolipoproteins: A-I, A-II

Question 7

Apo C-II

Answer 7

activates LPL

CM, VLDL

Question 8

Apo B-48

Answer 8

Intestinal marker

CM, IDL

Question 9

Apo B-100

Answer 9

Liver marker

VLDL, IDL, LDL

Question 10

Apo E

Answer 10

Target for liver remnant receptor

CM, VLDL, IDL

Question 11

Apo A-II

Answer 11

HDL marker

HDL

Question 12

Explain the difference between “lipoproteins” and “lipids”

Answer 12

• Lipids = cholesterol, TAGs
• Lipids are surrogate markers for lipoproteins
• So “dyslipidemias” really represent “dyslipoproteinemia”

Question 13

Friedewald equation

Answer 13

LDL-C = TC – HDL-C – (TG/5)

o Not accurate when assumptions break down:
• As TG levels increase since assuming TG/5 = VLDL-C
• So can’t use when TG > 400
• LDL-C includes IDL and Lp(a) cholesterol
• Misleadingly low when small LDL particle present
• Problem because LDL is main atherogenic lipoprotein!

Question 14

Exogenous lipid metabolism

Answer 14

o CMs from gut
• Contain Apo B-48, Apo C, Apo E
• TG core undergoes lipolysis via LPL → CM-Remnant
• CM-Remnant cleared by liver

Question 15

Endogenous lipid metabolism

Answer 15

o Liver produces VLDL
• Contain Apo B-100, Apo E, Apo C
• Lipolysis of TG core via LPL → IDL
o IDL can be shunted back to liver
o IDL can be further converted to LDL via HTGL
• LDL cleared by liver or deposited into tissues

Question 16

Dietary Cholesterol metabolism

Answer 16

o Enters small intestine via sterol transporter
o Free cholesterol is esterified via Acyl-CoA cholesterol Acyltransferase (ACAT)
o Packaged into CMs (with Apo B-48) → (via lymphatics) venous circulation
o CM’s interact with HDL to acquire Apo E and Apo C-II
o TG core hydrolyzed (via LPL) → converted to CM-Remnants
o CM-Remnant taken up by hepatic LDL receptor and LDL receptor-related protein (LRP)
o Bile salts: another form of cholesterol in intestine
• Absorbed via IBAT → liver → recycled
o Some Cholesterol exported via ABCG5/G8 exporter from enterocyte to intestine → adds to unabsorbed bile acid/cholesterol pool

Question 17

Extrahepatic cholesterol metabolism

Answer 17

o From de novo synthesis
o Back to liver via HDL
• HDL-C taken up via scavenger receptor B1 (SR-B1)

Question 18

Hepatic cholesterol metabolism

Answer 18

o Excreted in bile
• Most bile acids reabsorbed in ileum via intestinal bile acid transporter (IBAT)
o Or packaged with TG and put back into systemic circulation as nascent VLDL (with Apo B-100)
o Acquires Apo C-II and cholesterol esters form HDL → mature VLDL
o VLDL TG core hydrolyzed via LPL→ IDL/ VLDL remnant
• Apo C-II, phospholipids, and fatty acids transferred back to HDL
• IDL cleared by liver LDL-R or LRP (shunt pathway)
• IDL converted to LDL
o LDL is cleared by liver or tissues via LDL receptor

• LDL levels are highly regulated
• 50% body pool is cleared daily
• LDL-receptors clear 2/3 LDL
• Regulated by diet, hormones, genetics, and medications
• Suppressed by cholesterol (reduce HMG Co-A activity, decrease LDL-Receptor synthesis, and increase LCAT)
• Stimulated by cholesterol depletion, insulin, thyroxine
• Rest of LDL cleared by other pathways:
• Fluid-phase endocytosis
• Scavenger receptors (recognize and bind oxidized LDL → foam cells)

Question 19

Explain the key steps in high-density lipoprotein metabolism

Answer 19

• Functions of HDL:
o Reverse cholesterol transport: HDL brings cholesterol from extrahepatic tissues back to liver
o Anti-inflammatory effects
o Host defense and immunity (protection from endotoxins and trypanosomes)

• ABCA1 (aka cholesterol efflux regulatory protein CERP) transporter exports cholesterol from extrahepatic tissues to nascent HDL (contains Apo A-I)
• Cholesterol in nascent HDL is esterified by lecithin cholesterol acyltransferase (LCAT) → mature HDL particle

Mature HDL:

• Mature HDL can bind hepatic SR-B1 receptor → transfer of cholesterol ester from HDL to liver
o Cholesterol ester hydrolyzed → free cholesterol
• Mature HDL interacts with CM, VLDL, HDL via Cholesterol ester transfer protein (CETP)
o Synthesized in liver
o Catalyzes exchange of non-polar core components of lipoproteins
• VLDL, CM ←→ LDL, HDL
o High levels of TG, CM:
• CETP → loads LDL and HDL with TG (abnormal CE: TG ratios)
• Then HTGL hydrolyzes TG in LDL and HDL → low LDL-C and HDL-C levels (normal CE:TG ratios)
• Creates LDL and HDL particles that are small, dense, easily oxidized, poorly metabolized

Question 20

Relate abnormalities in lipoprotein metabolism to common clinical lipoprotein disorders

Answer 20

I: CM—LPL deficiency, Apo C-II deficiency

IIa: LDL–Apo C-II deficiency, FH, Defective Apo B-100, FCH

IIb: LDL and VLDL– FCH

III: IDL– Familial dysbetalipoproteinemia

IV: VLDL– Familial hypertriglyceridemia, FCH

V: CM & VLDL– Familial hypertriglyceridemia, Partial LDL, Apo C-II deficiency

Question 21

physical exam findings from hyperlipidemia and chylomicronemia syndrome

Answer 21

• Hyperlipidemia
o Arcus corneus: grayish hazy stripe on inside of iris
o Xanthelasmas: pale yellow fatty deposits on medial aspects of upper and lower eyelids
• Chylomicronemia Syndrome
o Eruptive xanthomata: on pressure points ex. Buttocks
o Tendon and tuberous (skin) xanthomata: in FH patients
o Lipemia retinalis: yellowed vessels in eyes

Question 22

Familial hypercholesterolemia

Answer 22

o Genetically deficient or defective LDL receptors
• None produced
• Receptors don’t migrate to surface of cell
• Defective LDL binding
• Internalization defect
o Autosomal dominant/co-dominant
• Elevated levels from birth
• Prevalence of homozygotes: 1/1,000,000
• Prevalence of heterozygotes: 0.2%
o TC values
• Heterozygotes: 325-450 mg/dL
• Homozygotes: 50-1000 mg/dL
o Manifestations:
• Tendon xanthomata in 70% by age 30
• Xanthelasmas, arcus corneus common
• Cardiac events (MI, SCD, aortic stenosis)
• Homozygotes: 1st decade
• Heterozygotes: men 3rd, women 4th decades
• Especially aggressive with tobacco use, low HDL-C, high Lp(a)

Question 23

Familial defective Apo B-100

Answer 23

o Mutation in gene for apo B-100
o Poor LDL binding to receptors
o Functionally similar to FH
o Incidence: 1/500
o LDL easily oxidized

Question 24

Familial combined hyperlipidemia

Answer 24

o Varying patterns of LDL-C and VLDL-C levels in families, with high Apo B-100
o Increases secretion of apo B-100 → increased VLDL and LDL
o 1/3 also have LDL abnormality
o Familial hyperapobetalipoproteinemia
o Increased atherogenicity
• LDL: long half-life, small and dense
• VLDL: cholesterol-enriched
• HDL: low levels, qualitative abnormalities
o Clinical features:
• US incidence: 2%
• Lipid abnormalities expressed after adolescence
• 1/3 have increased LDL-C, 1/3 increased TG, 1/3 both
• Many have decreased HDL
• Xanthelasmas, arcus corneus common
• Commonly associated with HT, type II DM, obesity in families

Question 25

Familial hypoalphalipoproteinemia

Answer 25

o Autosomal dominant defects in ABCA1 o HDL-C levels: 20-35 mg/dL o Cataracts, arcus corneus o Increased risk of CHD

Question 26

Identify the most common secondary causes of lipid disorders

Answer 26

**• Secondary hypercholesterolemia** o Hypothyroidism o Diabetes mellitus o Chronic renal disease o Obstructive liver disease o Obesity **• Secondary hypertriglyceridemia** o Alcohol use o Diabetes mellitus o Obesity o Chronic renal disease **• Secondary low HDL cholesterol** o Obesity o Diabetes mellitus o Chronic renal disease o Progestin use (birth control pills) **\*\*\* Most common cause of dyslipidemia is central/visceral obesity\*\*\***

Question 27

Pathophysiology of dyslipidemia with central obesity

Answer 27

*o Associated with neurohormonal changes:* • Increased “resistin” → Insulin resistance → hyperglycemia • Increased free fatty acid flux → hyperlipidemia, atherosclerosis, increased inflammation • Increased leptin → increased appetite • Increased inflammatory mediators (TNFα, IL-6, CRP) • Increases SNS → HT? • Increased angiotensin → HT? *o Pathophysiology*: Hormone sensitive lipase (HSL) inhibited by insulin • With insulin resistance → HSL causes release of glycerol and free fatty acids form adipose tissue • In liver → GNG (increased glucose) and increased VLDL production • VLDL undergoes lipolysis by LPL and HTGL → LDL • With high VLDL → lipid exchange by CETP → small dense LDL and HDL • Similar pathophysiology as FCH

Question 28

Major drugs for lipid disorders

Answer 28

**Mainly lower LDL-C:** Statins, Resins, Azetidinones **Mainly raise HDL-C and lower TG:** Niacin, Fibrates, Omega-3 fatty acids

Question 29

Statin drugs

Answer 29

* Best evidence for CVD reduction and safety * Reduce LDL-C by 20-60% * Also modestly reduce TG and increase HDL-C * HMG-CoA reductase inhibitors → reduce intrahepatic cholesterol pool → upregulation of hepatic LDL receptors and removal of LDL from blood; decrease VLDL production * Pleiotropic (not cholesterol-mediated) effects: inhibition of isoprenylation of small GTP binding proteins Rho, Ras, and Rac * May contribute to CVD reduction * **Side effects**: (dose-dependent) myalgia/myopathy, abnormal liver function tests * **Contraindications**: liver disease, pregnancy Class X, caution in combination with fibrates (increased risk of myopathy)

Question 30

Resins

Answer 30

bile acid binding resins or sequestrants • Modest evidence for CVD reduction; long-term safety • Major effect: reduce LDL-C 15-30% • Modest increase in TG, increase in HDL-C • Mechanism: block bile salt absorption in ileum → reduces intrahepatic cholesterol pool → upregulates hepatic LDL receptors and removal of LDL from bloodstream • Compensatory increase in HMG CoA Reducatase • Limits effectiveness • Works best with statins • **Side effects**: (dose dependent): • Abdominal discomfort and constipation • Decrease absorption of other drugs • Reduce absorption of fat soluble vitamins **• Contraindications** • Bowel or biliary obstruction • Elevated TG (especially \>200 mg/dL) • Multiple, complex medication regimens

Question 31

Azetidinones

Answer 31

(ezetimibe) • No evidence for CVD reduction or long-term safety • Major effect: reduction in LDL-C 14-20% • Minimal decrease in TG, minimal increase in HDL-C • **Mechanism**: block absorption of cholesterol in small intestine by inhibiting Niemann-Pick C1-like 1 protein (NPC1L1) → reduces intrahepatic cholesterol pool → upregulation of hepatic LDL receptors and removal • Compensatory increase in HMG CoA Reductase so best with statins • Well-tolerated by most • **Contraindications**: severe liver disease

Question 32

Niacin

Answer 32

• Modest evidence for CVD reduction; long term safety • Available as prescription or dietary supplement • **Major effects** (used in combined or low HDL disorders) • Increases HDL-C 15-30% • Reduces TG by 20-50% • Reduces LDL-C by 10-30% (at higher doses) **• Complex mechanisms:** • Reduces lipolysis from adipocytes → less free fatty acid flux, less VLDL synthesis • Reduces VLDL syntheses by inhibiting diacylglycerol acyltransferase (DGAT2) • Reduces apo A-1 catabolism (while allowing removal of cholesterol from HDL) **• Side effects** (dose dependent) • Flushing and itching (reduced with aspirin) • Abdominal pain, ulcers • Hyperglycemia • Hepatotoxicity • Gout • Myalgia/myopathy (especially with statins) **• Contraindications** • Liver disease • Gout • Uncontrolled type II DM • Pregnancy class C (avoid use in pregnancy)

Question 33

Fibrates (fibric acid derivatives)

Answer 33

• Modest evidence for CVD reduction (best in patients with low HDL-C or high TG) • Modest long-term safety record • Major effects (used if very high TG \> 500 mg/dL) to prevent pancreatitis • Reduces TG 20-50% • Increases HDL-C 10-20% • Reduces LDL-C by 5-20% if TG not high; may increase if high TG (since cholesterol is transferred from VLDL to LDL) **• Complex mechanism** • Activates PPAR-α → synthesis of apo A-I and A-II → HDL synthesis • Activates LPL and reduces apo CIII (LPL inhibitor) → hydrolysis of TG and VLDL • Stimulates hepatic fatty acid uptake and catabolism by β-oxidation → reduces TG synthesis, VLDL production **• Major side effects** • Abdominal pain • Gall stones • Increased creatinine • Myalgia/myopathy, especially with statins **• Contraindications** • Liver disease • Severe kidney disease (especially fenofibrate) • Gall stones • Caution with statins (fenofibrate may be safer) • Pregnancy class C (avoid in pregnancy)

Question 34

Omega-3 fatty acids in fish oils

Answer 34

• Modest evidence for CVD event reduction and long term safety at low doses and as dietary intervention • Prescription or dietary supplement • **Lipid effects** (dose dependent, need ≥3-4 g/day) • Reduces TG 20-50% • Modest effects on HDL-C, related to TG reduction • LDL-C may increase or not change **• Complex mechanisms** • Inhibits DGAT • Reduces lipolysis • Stimulate hepatic fatty acid catabolism by β-oxidation → reduces TG synthesis **• Major side effects** • Eructation, flatulence • Abdominal pain • Bruising, bleeding **• No major contraindications **

Question 35

Guiding principles in lipid medical treatment

Answer 35

• Guiding principle: intensity of therapy should be adjusted to patient’s risk of a CHD event • So use CHD risk to set goals o **Primary goal**: LDL-C UNLESS TG \>500mg/dL • Then use TG as primary goal o **Secondary goal**: non-HDL-C (when TG ≥200 mg/dL) • Non-HDL-C = TC minus HDL-C • Used because when TG ≥200, LDL-C can underestimate LDL particle concentration • Includes all cholesterol in atherogenic lipoproteins • Strongly correlated with LDL particles and Apo B-100 • Better predictor of CVD events than LDL-C • Non-HDL-C target = LDL-C target + 30 mg/dL

Question 36

LDL-C goals based on risk category

Answer 36

High risk: \<100 (\<70 optional) Moderately high: \<130 Moderate: \<130 Low: \<160 \*\*\*Consider drug therapy for all high- or moderately high-risk individuals above their LDL-C or non-HDL-C

Question 37

Medication Sequence according to lipid pattern

Answer 37

* *For TG \<200 mg/dL** - -statin - -add niacin, BAS, or ezetimibe - -add niacin, BAS, or ezetimibe * *For TG 200-499:** - -statin or niacin - -Statin + niacin - -add ezetimibe * *For TG \>500:** - -niacin, fish oils, or fibrate - -combination of niacin, fish oils, or fibrate - -add 3rd TG-lowering drug, consider adding a statin