Disorders Of Lipid Metabolism

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Tangier Disease

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Basic Cause: Extremely rare autosomal recessive disorder characterized by substantially reduced HDL levels.

Biochemical Cause: Caused by a mutation in the gene that encodes for CERP (ABCA1). [CERP = Cholesterol efflux regulatory protein. Facilitates efflux of free cholesterol particles from cells into HDL.]

Effect: Symptoms include [plasma HDL] <5 mg/dL, low total plasma cholesterol (below 150 mg/dL), & normal or high plasma triglycerides. Neuropathy. Enlarged, orange-colored tonsils (foam cells).

Treatment: No specific treatment has proven to be effective.

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Familial Hypercholesterolemia

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Basic Cause: Monogenic, autosomal dominant disorder caused by a mutation in the LDL receptor pathway.

Biochemical Cause: [Defective LDL receptors: several fold higher LDLs circulating, cholesterol cannot get into cells efficiently - no negative feedback suppression of cholesterol synthesis in the liver]. {Ex...} PCSK9 is part of normal LDL receptor pathway. Binds to LDL receptor & directs it to lysosome for degradation, when high intracellular cholesterol. Rare mutations increase its protease activity, reducing LDL receptor levels & reducing the uptakes of cholesterol into cells - more circulates.

Effect: Xanthoma. Hypercholesterolemia or mixed hyperlipidemia. Homozygotes do not survive into teens without liver transplant. Increased CVD risk. Increased circulating LDLs and cholesterol.

Treatment: Diet & exercise, cessation of smoking. Statins (inhibit HMG CoA reductase; up-regulate expression of cell-surface LDL receptors - lower total cholesterol & LDL cholesterol...HMG CoA reductase is the rate-determining enzyme in the cholesterol biosynthesis pathway). Bile acid sequestrants (lower total cholesterol & LDL cholesterol). Niacin (lowers VLDL cholesterol & increases HDL cholesterol). Fibrates (usually used in conjunction with other lipid lowering agents - to raise HDL cholesterol & lower VLDL cholesterol).

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Familial Combined Dyslipidemia (Hyperlipidemia)

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Basic Cause: Autosomal dominant, affects 2% of North American population - most common cause of coronary artery disease in US. Overweight, diet high in fat, lack of exercise.

Biochemical Cause: Decreased LDL receptors - affects lipoprotein endocytosis, & over-production of apoB100 - affects LPL activity. Results in increased production of VLDL. Sometimes increased LDL levels are observed, depending on the efficiency of LDL formation, uptake, or both.

Effect: Increased CVD risk. Angina, high LDLs, VLDLs & triglycerides, low HDLs. Hypercholesterolemia or mixed hyperlipidemia.

Treatment: Diet & exercise, cessation of smoking. Statins (inhibit HMG CoA reductase; up-regulate expression of cell-surface LDL receptors - lower total cholesterol & LDL cholesterol...HMG CoA reductase is the rate-determining enzyme in the cholesterol biosynthesis pathway). Bile acid sequestrants (lower total cholesterol & LDL cholesterol). Niacin (lowers VLDL cholesterol & increases HDL cholesterol). Fibrates (usually used in conjunction with other lipid lowering agents - to raise HDL cholesterol & lower VLDL cholesterol).

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Other Causes of Hyperlipidemias...

Lipids & Type II Diabetes/Obesity/Alcoholism

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Increased VLDL synthesis & consequent increase in IDL concentration.

LDL cholesterol is often normal; however, diabetic LDL may be more atherogenic b/c of changes in their size & density.

Diabetes/obesity also characterized by decreased HDL cholesterol. In contrast, alcohol abuse raises HDL cholesterol.

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Atherosclerosis

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Atherosclerosis: Narrowing or complete occlusion of the arterial lumen ("hardening of the arteries". Major cause of CVD - a thrombus that completely occludes the arterial lumen causes tissue necrosis resulting in a myocardial infarction of stroke.

Atherogenesis is a multifactorial process...

[LDLs pass through damaged endothelium into the vascular wall, & become oxidized in the extracellular space. Oxidized apoB100 binds to scavenger receptors expressed on macrophages, which become overloaded with lipid - change into foam cells, which form yellow patches in the arterial wall called "fatty streaks". Dying foam cells release lipid that pools w/in the intima & become centers of atherosclerotic plaques. Stimulation of inflammation. Changes in behavior of VSMC disrupts the normally ordered structure of the vessel wall.]

1. Endothelial Dysfunction

Excess lipoproteins, hypertension, diabetes,or cigarette smoke. Damage is initially functional; loss of anticoagulant properties, increased permeability, loss of cell repellant property, expression of adhesion molecules on surface, & decreased NO production. Later, the endothelium may become damaged or completely destroyed.

2. Lipid Deposition

Small, dense LDLs are considered to be an emerging risk factor for CVD. Development of these can be inherited. Lifestyle can also play important role in formation. Risk factors include: high carb. intake, trans fat intake, uncontrolled diabetes, high triglycerides, low HDL, metabolic syndrome. LDL receptor gene expression regulated by [intracellular cholesterol]. Scavenger receptors on macrophage have no feedback regulation & can overload cell with their ligands. Conglomerates of these foam cells are visible in arterial lumen as yellow patches - fatty streaks. Necrotic foam cells release LDLs, which pool in intima & become center of atherosclerotic plaques.

3. Inflammation

Monocyte & lymphocyte entry into & activation w/in the intima. No specific Ag capable of initiating this response identified. Molecular mimicry proposed b/w Ags involved in atherosclerosis & pathogens. Characterized by elevated levels of plasma C-reactive protein (CRP) - acute phase protein produced in liver in response to pro-inflammatory cytokines. CRP levels can be used to predict CVD risk.

4. VSMC Migration & Proliferation

GFs (secreted by the damaged endothelium & macrophages) induce VSMC migration &growth towards the lumen of the vessel - in efforts to stabilize the forming plaque. Synthesize ECM like collagen, which is deposited in the growing plaque. Normally ordered structure of the arterial wall becomes completely disrupted. Growing plaque may protrude into the lumen,disrupting blood flow. Can be exposed to TF on subendothelial cells & also macrophages- initiating coagulation response - CVD.

Vascular calcification is highly correlated with presence of atherosclerosis.

Atherosclerotic plaque growth:

Rupture of the plaque due to secretion of enzymes by macrophages, which degrade ECM present in fibrous cap; and/or inhibition of VSMC collagen synthesis. Exposure of blood to the interior of the fibrous cap, which contains TF (expressed on activated monocytes/macrophages & VSMCs). Coagulation & platelets are activated - thrombus formation. PDGF released from activated platelets contributes to proliferation of VSMC (& other subendothelial cells). Plaque growth can be accelerated by repeated cycles of rupture & thrombosis.

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Trans Fatty Acid Consumption

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Small amounts of TFAs are found in nature, but most are created through hydrogenation.

TFAs have been associated with development of CVD, cancer, inflammation, & Type II Diabetes.

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Diabetic Ketoacidosis

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Basic Cause: Typically associated with type 1 diabetes. [Ketogenesis: During fasting, liver uses fatty acids as source of energy for gluconeogenesis]

Biochemical Cause: Glucagon promotes release of glucose from liver & fatty acids from adipose tissue. Shortage of insulin - can't suppress above process. Acidic ketone bodies produce from extensive fatty acid oxidation.

Effect: Potentially life-threatening symptoms; vomiting, dehydration, deep gasping breathing, confusion, coma.

Treatment:

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Carnitine Deficiency

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Basic Cause: Defects in long-chain fatty acid oxidation. [Disease of lipid metabolism - body unable to utilize fats for energy]

Biochemical Cause: Carnitine assists in transport of long chain acyl CoA molecules across inner mitochondrial membrane into mitochondrial matrix.

Effect: Life-threatening, featuring hypoketotic hypoglycemia, liver damage, hyperammonemia, cardiomyopathy, & hypotonia.

Treatment: Carnitine supplementation, frequent high-carbohydrate feeding, & avoiding fasting.

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Medium-chain Fatty Acyl CoA Dehydrogenase Deficiency (MCAD)

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Basic Cause: Autosomal recessive deficiency of MCAD, which processes medium-chain fatty acids. [Disease of lipid metabolism - inability to oxidize medium chain fatty acids.]

Biochemical Cause: Deficiency in medium-chain fatty acyl CoA dehydrogenase.

Effect: Typical presentation: infant/child has hypoketonic hypoglycemia, is vomiting, and is lethargic. High concentrations of medium chain carboxylic acids & acyl carnitines in plasma & urine. Hyperammonemia may be present - liver damage.

Treatment: Increase protein & carb intake, decrease fat intake, avoid fasting.

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Long-chain Hydroxyacyl CoA Dehydrogenase Deficiency (LCHAD)

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Basic Cause: Autosomal recessive disease of lipid metabolism - inability to oxidize long chain fatty acids.

Biochemical Cause: Deficiency in the 3rd step of beta-oxidation, the oxidation of a hydroxyl to a ketone, due to LCHAD deficiency.

Effect: Long-chain or partially metabolized fatty acids accumulate in liver, heart, musculature, kidneys, retina, & interfere with their functions. Symptoms generally appear during infancy/early childhood - Lethargy, hypoglycemia, hypotonia, eye abnormalities, liver damage.

Treatment: Carnitine supplementation, frequent feeding, avoid fasting.

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Lipid Abnormalities from Alcoholism

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(Ethanol cannot be excreted, & must be metabolized, primarily by the liver. In the human body, ethanol is first oxidized to acetaldehyde, & then to acetic acid. The first step is catalzyed by alcohol dehydrogenase in the cytoplasm, & the 2nd step by aldehyde dehydrogenase in the mitochondria.)

*Fatty liver

*Excessive triglyceride synthesis

*Hypertryglyceridemia

*Hypercholesterolemia

*Defective plasma cholesterol esterification

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CVD

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Risk Factors: Male sex, age, smoking, high plasma cholesterol (high LDLs), low plasma HDLs, hypertension, obesity, sedentary lifestyle, types I & II diabetes.

Atherosclerosis is major cause of M.I. & stroke.

CVD Treatments: Smoking cessation, diet low in saturated fats, exercise, decrease alcohol consumption, control BP through diet & drugs.

Aspirin or other inhibitors of platelet function. Warfarin or other antithrombotic agents.

Surgical Interventions: Angioplasty, stent, bypass surgery.