**VLDL
• Source
• Composition (Apoprotein, TG:Chol)
• Functional Role
*
Source:
• Made by Liver (endogenous path)
Composition:
• ApoB-100, Apo CII, Apo CIII, Apo A-V
• Carries 5:1 ratio of Triglyceride to Cholesterol
Functional Role:
• Delivers TGs and Chol. to Adipose Tissue and Muscle
**LDL
• Source
• Composition (Apoprotein, TG:Chol)
• Functional Role
*
Source:
• Breakdown Product of IDL
Composition:
• ApoB-100, Apo(a)
• LESS than 5% Triglyceride (almost solid cholesterol)
Functional Role:
• Returns Cholesterol to Liver or
• Puts more cholesterol in Peripheral Tissues (if overloaded)
**Chylomicrons
• Source
• Composition (Apoprotein, TG:Chol)
• Functional Role
*
Source:
• made of TGs and Cholesterol that is absorbed in the Proximal Jejunum (exogenous path)
Composition:
• Apo-48, ApoC (II, III), ApoA (I, II, V), Apo E (on remnants)
• has 10:1 ratio of Triglyceride to Cholesterol
Functional Role:
• Secreted into the blood from intestines and Delivers Fat to Tissues via interactions with LPL receptors
**Lp(a)
• Source
• Composition (Apoprotein, TG:Chol)
• Functional Role
*
Source:
• Liver
Composition:
• ApoB-100
• Apo(a) - Aberrent form of Thromboplastin
Functional Role:
• VERY ATHERLOGENIC
**What are the desirable levels of:
• LDL-C
• HDL-C
• Triglyceride
*
LDL:
• Less than 130
HDL:
• Men = greater than 40
• Women = greater than 50
Triglycerides:
• Less than 120
**Typically want TOTAL CHOLESTEROL under 200
**Primary Chylomicronemia
- Inheritance
- Lipoprotein Abnormality
- Pathophysiology
- Clinical Characteristics
- Complications
*
Inheritance:
• Recessive
Lipoprotein Abnormality:
• ApoCII or LPL defect
Pathophysiology:
• ApoCII binds LPL to release TGs into tissues
• Disruption in this interaction means TGs build up in the blood
Clinical Characteristics:
• Usually found in Kids
• CHYLOMICRONS and VLDL elevated (in the 10,000 range)
Complications:
• PANCREATITIS
• Patients may get Xanthomas on chest and back
**Familial Hypertriglyceridemia
- Lipoprotein Abnormality
- Pathophysiology
- Clinical Characteristics
- Complications
*
Lipoprotein Abnormality:
• none, this is a defect in LPL
Pathophysiology:
• LPL is needed to take TGs out of VLDL
• If its absent the VLDL and TGs inside it just build up
Clinical Characteristics:
• Adults with TGs in the 1000s
• AND have elevated VLDL
Clinical Complications:
• Pancreatitis
• Often seen in diabetics
**Familial Dysbetalipoproteinemia
- Lipoprotein Abnormality
- Pathophysiology
- Clinical Characteristics
- Complications
*
Lipoprotein Abnormality:
• ApoE defect (E2/E2 alleles)
Pathophyiology:
• ApoE is used by Chylomicron remnants, IDL, and HDL to bind to the LDL receptor
• MOST IMPORTANTLY IDL never gets converted to LDL
Clinical Characteristics:
• VLDL and Chylomicron remnants High
• ELEVATED CHOLESTEROL AND TG in 1:1 ratio (~250-300)
**Familial Combined Hyperlipidemia (FCH)
- Inheritance
- Lipoprotein Abnormality
- Pathophysiology
- Clinical Characteristics
- Complications
*
Inheritance:
• Autosomal Dominant
Lipoprotein Abnormality:
• Overproduction of apoB
Pathophysiology:
• Overproduction of ApoB-100 leads to too many VLDL particles
• Ultimately this cause high cholesterol
Clinical Characteristics:
• STRONG FAMILY HISTORY of EARLY athlerosclerosis
• Variably high VLDL, LDL, or Both
Complications:
• Premature athlerosclerosis
**Familial Hypercholesterolemia (FH)
- Inheritance
- Lipoprotein Abnormality
- Pathophysiology
- Clinical Characteristics
- Complications
*
Inheritance:
• Autosomal Dominant
Lipoprotein Abnormality:
• LDL Receptor or ApoB defect
Pathophysiology:
• Decreased Receptor Mediated Removal of LDL from plasma
Clinical Characteristics:
• Young, skinny people with unusually high LDL
• LDL 400-600
Complications:
• Homozygotes = Artherlosclerosis by age 12
**Secondary Causes of Hyperlipoproteinemia
* • HypOthyroidism • Kidney or Liver Disease • Medications • Excess Calories and Simple Sugars • Genetic Factors
**What is the functional Role of:
• LDL-receptor
*
• LDL receptor binds ApoB-48 and pulls out Cholesterol
**What is the functional Role of:
• Apolipoproteins
*
• In general these mediate binding events with receptors that cause depletion of cholesterol or TG from Lipoproteins and Chylomicrons
**What is the functional Role of:
• CETP
*
Cholesteryl ester transfer protein - transfers cholesterol and TGs between (V)LDL particles and HDL
• Makes HDL larger and more susceptible to uptake by the liver via SRB1 receptor
**What is the functional Role of:
• ApoCII
*
• Found on Chylomicrons, VLDL, and HDL
• Co-factor for LPL - so it needed to drop TGs off in tissues
**What is the functional Role of:
• ApoCIII
*
• Found on Chylomicrons, VLDL, and HDL
• INHIBITS lipoprotein binding to receptors
**What is the functional Role of:
• ApoB
*
• Either ApoB-48 (chylomicrons) or Apo-100 (everything else) are the structural protein for all fat carrying particles
• LIGAND FOR BINDING LDL receptor
**What is the functional Role of:
• PPAR-a
*
• Activates Genes such as Apo CII and deactivates genes such as Apo CIII allowing for REDUCTION IN SERUM TGs
**What dietary Factors influence hyperlipidemia?
*
• Alcohol intake
• Cholesterol and Saturated/Trans-Fat intake
• Simple Sugar Intake
**What are the principles of Dietary management of hyperlipidemia?
*
Cholesterol:
• Reduce SATURATED and TRANS-FATS
TGs:
• Total Fat
• Alcohol
• Excess Calories
What is the major carrier of cholesterol in the plasma?
LDL
T or F: Peripheral Tissues rely heavily on LDL to acquire appropriate amounts of Cholesterol.
False, most tissues can synthesize the cholesterol they need by themselves
What happens to chylomicron remnants?
• what are the risks of system overload with these?
- Return to the liver to give TGs via the LDLR
* These are Athlerogenic particles so system overload can lead to CV disease
LDL and HDL are almost purely made of cholesterol, what makes LDL bad and HDL good?
LDL:
• Bad because it just circulates and keeps dumping of cholesterol into tissues
HDL:
• Has Apoproteins that allow it pull cholesterol out of macrophages and return cholesterol to the liver
What is the Friedwald Formula?
• what is it used for?
• Used to Calculate LDL-Cholesterol
Formula:
• TC - (VLDL-C (TG/5) + HDL-C) = LDL
HDL
• Source
• Composition (Apoprotein, TG:Chol)
• Functional Role
Source:
• Liver
Composition:
Functional Role:
• Retrieves Cholesterol from the Artery Wall and Inhibits the oxidation of atherogenic lipoproteins
When are patients at risk of developing pancreatitis?
• When TGs get above 1000
Differentiate Primary Chylomicronemia and Familial Hypertriglyceridemia?
Chylomicronemia:
• involves mostly defective removal of chylomicrons
Familial Hypertriglyceridemia:
• Involves mostly defective removal of VLDL
Functional Role of ApoE.
• what kind of particles is it associated with?
ApoE
• Ligand for binding to the LDL receptor
Particle association:
• Chylomicron Remnants, IDL, HDL
How is familial Dysbetalipoproteinemia usually diagnosed?
• why is this the case?
- People will have high TGs and cholesterol and Dr. will prescribe a statin
- The statin ends up having only a minimal effect because the amount of LDL receptor being greater won’t change the fact that ApoE can’t bind to it.
Which of the Primary Hyperlipoproteinemias is Autosomal Dominantly inherited?
• Familial Combined Hyperlipidemia (FCH)
What similarities in pathophysiology exist between Primary Chylomicronemia and Familial Hypercholesterolemia?
Both are defects of lipid actually getting into tissue for LPL primary issue is getting into peripheral tissues for LDL problems getting back to the liver are an issue
Primary Chylomicronemia
• Defect between apoCII and LPL
Familial Hypercholesterolemia
• Defect between apoB and LDL receptor
What is the Optimal goal for LDL?
• what about in patients with atherosclerotic disease?
Optimal = 100 mg/dl
Atherosclerotic Disease = 70 mg/dl
What are some kidney disorders that might be a secondary cause of hyperlipidemia?
- Nephrotic Syndrome
* Hypoalbuminemia - albumin naturally turns down levels of VLDL so if it gets turned down VLDL will go up
What are some Liver Diseases that might cause hyperlipidemia?
- Hepatitis - too many lipoproteins made
* Biliary Disease - bile goes back into the circulation
What are some medication that can cause hyperlipidemia?
- Estrogen
- Beta Blockers
- Thiazide Diuretics
If someone has high cholesterol that is asymptomatic, how should you treat them?
• what if they are symptomatic?
- Asymptomatic - Modify their diet to get LDL-C below 100 mg/dl
- CV disease then modify their diet to get LDL-C below 70 mg/dl
What is the job of the ABCG1 transporter?
• Moves Cholesterol from Macrophages into HDL particles so that Cholesterol can be returned to Liver
What are some physical finding that are pathopneumonic for Familial Hypercholesterolemia?
- Achilles Tendon Xanthomas
- Xanthomas on extensor tendons of hand
Xanthomas around the eyes are not as indicative
What would refrigerated serum look like in a patient with:
• Primary Chylomicronemia
• Familial Hypercholesterolemia
Primary Chylomicronemia:
• Tons of chylomicrons would rise to the top and harden
Familal Hypercholesterolemia:
• Plasma would be cloudy from elevated VLDL
What aspect of treating hyperlipidemia actually causes the reduction in risk for people who have had acute coronary events?
• Mitigation of Inflammatory activity of Macrophages
How are people with Hypertriglyceridemia typically treated?
TG depleting agents:
• Fibrate
• Niacin
What is the primary method of treatment for people with Hypertriglyceridemia?
• DIETARY MAINLY
TG depleting agents:
• omega-3
• Fibrate
• Niacin
What is the primary treatment for people with Familial Dysbetaliproteinemia?
HIGH TGs and Cholesterol
HIGH TGs:
• Niacin and Diet Treated
HIGH cholesterol:
• Statins
What are some dietary changes that can be made to lower cholesterol?
• Triglycerides?
Cholesterol:
• Saturated Fats
• Trans Fats
TGs:
• Total Fats
• EtOH
• Excess Calories
Eat Complex Carbs and Fiber