Dyslipidemia Summary

Objectives

  • Composition of lipoproteins and apolipoproteins.

  • Characteristics of lipoprotein subclasses.

  • Exogenous and endogenous lipid transport pathways; roles of enzymes and proteins.

  • Clearance of LDL-C from plasma; importance of ApoB, LDLR, and PCSK9.

  • Reverse cholesterol transport pathway and atherosclerosis.

  • Classification of lipid disorders and related genetic deficiencies.

  • Clinical signs, symptoms of dyslipidemia; disease presentation.

  • Pharmacology of lipid-lowering agents: Statins, Ezetimibe, PCSK9 inhibitors, Fibrates, Niacin, Bile acids, Omega 3 fatty acids, Bempedoic Acid, Lomitapide.

Lipoproteins Overview

  • Lipoproteins are complex particles composed of a hydrophobic core (triglycerides and cholesterol esters) surrounded by a hydrophilic shell (phospholipids, unesterified cholesterol, and apolipoproteins).

  • They transport fats (triglycerides) and cholesterol throughout the bloodstream.

  • Named based on their density and protein content: High-Density Lipoproteins (HDL) are the densest due to their high protein content, while Low-Density Lipoproteins (LDL) are less dense.

  • Subclasses differ in size, density, and lipid/protein composition, reflecting their specific roles in lipid metabolism:

    • Chylomicrons: Formed in the intestine, carry dietary lipids. Largest and least dense.

    • Protein: ≈≈ 1%

    • Triglycerides: ≈≈ 88%

    • Cholesterol Esters: Trace

    • Very-Low-Density Lipoproteins (VLDL): Synthesized in the liver, transport endogenous triglycerides.

    • Protein: ≈≈ 10%

    • Triglycerides: ≈≈ 56%

    • Cholesterol Esters: ≈≈ 15%

    • Intermediate-Density Lipoproteins (IDL): Transient particles formed from VLDL catabolism, precursors to LDL.

    • Protein: ≈≈ 18%

    • Triglycerides: ≈≈ 23%

    • Cholesterol Esters: ≈≈ 34%

    • Low-Density Lipoproteins (LDL): Formed from VLDL/IDL, primarily carry cholesterol to peripheral tissues. Often referred to as "bad cholesterol."

    • Protein: ≈≈ 20%

    • Triglycerides: ≈≈ 13%

    • Cholesterol Esters: ≈≈ 48%

    • High-Density Lipoproteins (HDL): Synthesized in the liver and intestine, involved in reverse cholesterol transport. Often referred to as "good cholesterol."

    • Protein: ≈≈ 50%

    • Triglycerides: ≈≈ 13%

    • Cholesterol Esters: ≈≈ 30%

Apolipoproteins

  • Apolipoproteins are proteins found on the surface of lipoproteins, crucial for their structure, metabolism, and interactions with enzymes and receptors.

  • They serve as enzyme co-factors/inhibitors, structural components, and ligands for cell surface receptors.

  • Key Apolipoproteins and their primary functions:

    • ApoA-I: Principal apolipoprotein of HDL. Activates Lecithin-Cholesterol Acyltransferase (LCAT), which esterifies cholesterol, trapping it within HDL and promoting cholesterol efflux from peripheral cells.

    • ApoB-48: Unique to chylomicrons. Essential for chylomicron assembly and secretion from intestinal enterocytes.

    • ApoB-100: Found on VLDL, IDL, and LDL. Crucial for the structural integrity of these lipoproteins and serves as the primary ligand for the LDL receptor (LDLR), enabling uptake of LDL particles by cells.

    • ApoC-II: Present on chylomicrons and VLDL. A required co-factor for Lipoprotein Lipase (LPL) enzyme, which cleaves triglycerides from these particles in capillaries of muscle and adipose tissue.

    • ApoE: Found on chylomicron remnants, VLDL, and IDL. Serves as a ligand for the LRP1 (LDL Receptor-Related Protein 1) and LDLR, mediating the hepatic uptake of chylomicron remnants and IDL.

Transport Pathways

  • Exogenous Pathway (Dietary Lipids):

    • Chylomicrons are assembled in the intestine from dietary triglycerides and cholesterol, incorporating ApoB-48.

    • They enter the lymphatic system and then the bloodstream, acquiring ApoC-II and ApoE from HDL.

    • In capillaries, ApoC-II activates LPL, which hydrolyzes triglycerides in chylomicrons, releasing fatty acids for tissue uptake.

    • As triglycerides are removed, chylomicrons become smaller chylomicron remnants, losing ApoC-II but retaining ApoE and ApoB-48.

    • Chylomicron remnants are then rapidly cleared by the liver via interaction of ApoE (and ApoB-48) with hepatic receptors (LDLR and LRP1).

  • Endogenous Pathway (Hepatic Lipids):

    • VLDL particles are synthesized in the liver, packaging endogenous triglycerides and cholesterol with ApoB-100.

    • VLDL is secreted into the bloodstream, gaining ApoC-II and ApoE from HDL.

    • LPL, activated by ApoC-II, hydrolyzes triglycerides in VLDL, leading to the formation of IDL (Intermediate-Density Lipoproteins).

    • IDL can either be taken up by the liver (via ApoE binding to LDLR/LRP1) or further metabolized by hepatic lipase to form LDL particles, which primarily contain cholesterol esters and ApoB-100.

  • LDL Clearance:

    • The majority (about 70%) of plasma LDL-C is cleared by the liver through the LDL receptor (LDLR) pathway.

    • ApoB-100 on LDL binds to the LDLR on the surface of hepatocytes and other peripheral cells, initiating receptor-mediated endocytosis.

    • Inside the cell, LDL is degraded, and the receptors are typically recycled back to the cell surface.

    • PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) plays a critical role in regulating LDLR levels. PCSK9 binds to the LDLR on the cell surface, leading to the lysosomal degradation of the receptor instead of its recycling, thereby reducing LDL clearance from plasma and increasing plasma LDL-C levels.

Reverse Cholesterol Transport

  • This pathway, primarily mediated by HDL, removes excess cholesterol from peripheral tissues and returns it to the liver for excretion or reprocessing, thereby preventing cholesterol accumulation in cells and reducing atherosclerosis risk.

  • Steps:

    1. Cholesterol Efflux: Nascent HDL (containing ApoA-I) interacts with the ABCA1 transporter (ATP-binding cassette transporter A1) on peripheral cells (e.g., macrophages) to pick up unesterified cholesterol and phospholipids.

    2. Cholesterol Esterification: ApoA-I activates LCAT, which esterifies the free cholesterol, trapping it in the HDL core and allowing HDL to grow in size and mature.

    3. Cholesterol Exchange: Cholesteryl Ester Transfer Protein (CETP) can exchange cholesterol esters from HDL for triglycerides from VLDL/LDL.

    4. Hepatic Uptake/Transfer: Mature HDL can deliver cholesterol directly to the liver via the Scavenger Receptor B1 (SR-B1). Alternatively, the cholesterol esters taken up by VLDL/LDL (via CETP) can then be cleared by the liver via their respective receptors.

  • HDL functions: Stimulates macrophage cholesterol efflux, enhances endothelial function, exhibits anti-inflammatory and antioxidant properties, and inhibits LDL oxidation, all contributing to its protective role against atherosclerosis.

Lipid Disorders Classification

  • Dyslipidemia refers to abnormal levels of lipids (cholesterol and/or triglycerides) in the blood.

  • Primary Lipid Disorders: Genetic or inherited conditions leading to dyslipidemia.

    • Familial Hypercholesterolemia (FH): An autosomal dominant disorder caused by mutations in genes encoding the LDL receptor (most common), ApoB-100, or gain-of-function mutations in PCSK9. Results in elevated LDL-C levels and premature atherosclerotic cardiovascular disease.

    • Familial Hypertriglyceridemia: Often polygenic, characterized by elevated triglyceride levels, potentially due to impaired LPL activity or increased VLDL production.

    • Familial Combined Hyperlipidemia: Characterized by elevated total cholesterol, LDL-C, and/or triglycerides.

  • Secondary Lipid Disorders: Acquired conditions resulting from lifestyle factors, other diseases, or medications.

    • Diet-induced: High intake of saturated and trans-fats, high dietary cholesterol, excessive simple carbohydrates, and alcohol can lead to elevated LDL-C and/or triglycerides.

    • Disease-induced: Hypothyroidism, nephrotic syndrome, chronic kidney disease, obstructive liver disease, diabetes mellitus (especially uncontrolled type 2), and obesity.

    • Drug-induced: Medications like thiazide diuretics, beta-blockers, corticosteroids, oral estrogens, protease inhibitors, and immunosuppressants can significantly impact lipid profiles.

  • Clinical Signs and Symptoms of Dyslipidemia: Often asymptomatic until complications arise. Severe cases may present with:

    • Xanthomas: Cholesterol deposits in tendons (tendinous xanthomas, e.g., Achilles tendon) or skin (eruptive xanthomas with hypertriglyceridemia).

    • Xanthelasmas: Soft, yellowish plaques on eyelids.

    • Corneal Arcus: A gray-white ring around the cornea, especially in individuals under 40 (arcus juvenilis) indicates significant hypercholesterolemia.

    • Pancreatitis: Severe hypertriglyceridemia (typically >10001000 mg/dL) significantly increases the risk of acute pancreatitis.

    • Premature Atherosclerotic Cardiovascular Disease (ASCVD): Manifestations include angina, myocardial infarction, stroke, or peripheral artery disease.

Pharmacology of Lipid-Lowering Agents

  • Statins (HMG-CoA Reductase Inhibitors):

    • Mechanism: Potently inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis in the liver.

    • Effect: Primarily reduce LDL-C (by increasing hepatic LDL receptor expression), moderate triglyceride lowering, and modest HDL-C increase. Considered first-line for most dyslipidemias.

  • Ezetimibe (Cholesterol Absorption Inhibitor):

    • Mechanism: Selectively inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein, located on the brush border of enterocytes, thereby blocking cholesterol absorption from the small intestine.

    • Effect: Reduces LDL-C, with a synergistic effect when combined with statins.

  • PCSK9 Inhibitors (Proprotein Convertase Subtilisin/Kexin type 9 Inhibitors):

    • Mechanism: Monoclonal antibodies (e.g., Alirocumab, Evolocumab) that bind to circulating PCSK9, preventing it from binding to and promoting the degradation of the LDL receptor.

    • Effect: Significantly increase the recycling and availability of LDL receptors on hepatocytes, leading to a substantial reduction in LDL-C.

  • Fibrates (PPAR-αα Agonists):

    • Mechanism: Activate Peroxisome Proliferator-Activated Receptor alpha (PPAR-αα), a nuclear receptor that regulates gene expression involved in lipid metabolism.

    • Effect: Primarily lower triglycerides (by increasing LPL activity and decreasing ApoC-III synthesis) and also increase HDL-C.

  • Niacin (Vitamin B3B3​/Nicotinic Acid):

    • Mechanism: Reduces hepatic synthesis and secretion of VLDL particles, leading to decreased production of LDL and significantly increasing HDL-C.

    • Effect: Lowers triglycerides and LDL-C, and increases HDL-C more effectively than other agents. Use is limited by common prostaglandin-mediated flushing.

  • Bile-Acid Sequestrants (Resins):

    • Mechanism: Highly positively charged polymers (e.g., Cholestyramine, Colesevelam) that bind negatively charged bile acids in the intestine, forming an insoluble complex that is excreted in feces.

    • Effect: Depletes the hepatic pool of bile acids, leading to increased synthesis of new bile acids from cholesterol, which in turn upregulates LDL receptor expression on hepatocytes and lowers LDL-C.

  • Omega-3 Fatty Acids (Fish Oil):

    • Mechanism: Exact mechanism complex, but involves reducing hepatic very-low-density lipoprotein (VLDL) triglyceride synthesis and increasing fatty acid oxidation in the liver.

    • Effect: Primarily lowers triglycerides (especially at high doses); some preparations may lead to a small increase in LDL-C.

  • Bempedoic Acid (ATP Citrate Lyase Inhibitor):

    • Mechanism: Inhibits ATP Citrate Lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway in the liver.

    • Effect: Reduces hepatic cholesterol synthesis, leading to upregulation of LDL receptors and a decrease in LDL-C levels. It is a prodrug requiring activation in the liver.

  • Lomitapide (Microsomal Triglyceride Transfer Protein Inhibitor):

    • Mechanism: Inhibits Microsomal Triglyceride Transfer Protein (MTP), an enzyme essential for the assembly and secretion of chylomicrons and VLDL in the intestine and liver, respectively.

    • Effect: Dramatically reduces the secretion of VLDL and chylomicrons, leading to significant reductions in LDL-C and triglycerides. Approved for homozygous familial hypercholesterolemia (HoFH), but use is limited by Gl and hepatic adverse effects.