Lipid Metabolism Flashcards
Explain the role of lipoproteins in atherogenesis.
• 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
Components of CM
Density <0.95
Diameter: 75-300
90-96% TAG
Apoplipoproteins: B-48, E, C-II
Components of VLDL
Density: 0.95-1.006
Diameter: 30-80
60% TAG
Apolipoproteins: B-100, E, C-II
Components of IDL
Density: 1.006-1.019
Diameter: 23-35
Apolipoproteins: B-48, B-100, E
Components of LDL
Density: 1.019-1.063
Diameter: 18-25
50% Cholesterol
Apolipoproteins: B-100
Components of HDL
Density: 1.063-1.21
Diameter: 5-12
20% cholesterol
Apolipoproteins: A-I, A-II
Apo C-II
activates LPL
CM, VLDL
Apo B-48
Intestinal marker
CM, IDL
Apo B-100
Liver marker
VLDL, IDL, LDL
Apo E
Target for liver remnant receptor
CM, VLDL, IDL
Apo A-II
HDL marker
HDL
Explain the difference between “lipoproteins” and “lipids”
- Lipids = cholesterol, TAGs
- Lipids are surrogate markers for lipoproteins
- So “dyslipidemias” really represent “dyslipoproteinemia”
Friedewald equation
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!
Exogenous lipid metabolism
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
Endogenous lipid metabolism
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
Dietary Cholesterol metabolism
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
Extrahepatic cholesterol metabolism
o From de novo synthesis
o Back to liver via HDL
• HDL-C taken up via scavenger receptor B1 (SR-B1)
Hepatic cholesterol metabolism
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)
Explain the key steps in high-density lipoprotein metabolism
• 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
Relate abnormalities in lipoprotein metabolism to common clinical lipoprotein disorders
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
physical exam findings from hyperlipidemia and chylomicronemia syndrome
• 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
Familial hypercholesterolemia
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)
Familial defective Apo B-100
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
Familial combined hyperlipidemia
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
Familial hypoalphalipoproteinemia
o Autosomal dominant defects in ABCA1
o HDL-C levels: 20-35 mg/dL
o Cataracts, arcus corneus
o Increased risk of CHD
Identify the most common secondary causes of lipid disorders
• 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***
Pathophysiology of dyslipidemia with central obesity
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
Major drugs for lipid disorders
Mainly lower LDL-C:
Statins, Resins, Azetidinones
Mainly raise HDL-C and lower TG:
Niacin, Fibrates, Omega-3 fatty acids
Statin drugs
- 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)
Resins
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
Azetidinones
(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
Niacin
• 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)
Fibrates (fibric acid derivatives)
• 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)
Omega-3 fatty acids in fish oils
• 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 **
Guiding principles in lipid medical treatment
• 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
LDL-C goals based on risk category
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
Medication Sequence according to lipid pattern
- *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
