Lipids and Lipoproteins

Lipids and Lipoproteins

Energy Metabolism

  • Clinical importance related to coronary heart disease (CHD):

    • A significant causal factor of death in affluent countries.

    • In the U.S., accounts for approximately 500,000 deaths per year.

    • Western diets compared to Asian diets show differing impacts on CHD.

    • International efforts are being implemented to minimize the effects of CHD on public health.

    • Focus is placed on improving the reliability and convenience of lipid assays.

Biological Roles of Lipids

  • Functions of lipids include:

    • Aiding in digestion.

    • Serving as a rich energy source.

    • Lipids have double caloric energy compared to equivalent amounts of proteins or carbohydrates.

    • Efficiently storing excess calories.

    • Providing insulation that allows for nerve conduction or prevents heat loss.

    • Cholesterol acts as a precursor for the synthesis of steroid hormones.

    • Serving as crucial components of cell membranes and various cell structures.

General Characteristics of Lipids

  • Lipids are composed of the same elements as carbohydrates, but they have a lower proportion of oxygen (primarily C-H bonds), making them a rich energy source.

  • Hydrophobic nature:

    • Generally insoluble in water but soluble in organic solvents such as alcohol, ether, carbon tetrachloride, and benzene.

    • The water-repelling characteristic of certain lipids is vital for cellular membrane function.

Major Lipids in Human Cells

  • Types include:

    • Triglycerides

    • Phospholipids

    • Cholesterol

    • Cholesteryl esters

  • Transported via the bloodstream in lipoprotein form.

Composition of Lipids

  • Formation of Fats:

    • Fats are produced through the reaction of an organic acid (fatty acid) with an alcohol (glycerol).

    • Fatty acids are linear chains of C-H bonds that end with a –COOH group.

    • Most fatty acids are synthesized in the body from carbohydrate precursors, with two being essential and needing to be obtained from dietary plants.

Fatty Acids

  • In plasma:

    • Very few free fatty acids are present; most are bound to albumin.

    • The majority are found as components of triglycerides and phospholipids.

    • Diet typically consists of “long-chain” fatty acids (>12 carbon atoms) in even-numbered chains.

    • Some carbon atoms create C=C double bonds rather than C-H bonds, leading to unsaturated fats.

Unsaturated Fatty Acids

  • Types:

    • Monounsaturated: contains one C=C double bond.

    • Polyunsaturated: consists of two or more double bonds.

    • Unsaturated fatty acids with a “cis” configuration tend to be more liquid than saturated fatty acids due to molecular bending, resulting in oils.

Trans Fatty Acids

  • Unsaturated fatty acids with a “trans” configuration do not bend and resemble saturated fats.

  • Result from chemical hydrogenation during food processing and have been shown to increase the risk of coronary heart disease.

Saturated Fat

  • Defined by the absence of C=C double bonds; therefore, the structure is unbent.

  • Generally more atherogenic than unsaturated fats.

Triglycerides

  • Composed of three fatty acids attached to one glycerol molecule via ester bonds, with each fatty acid potentially differing in structure.

  • Sources can be dietary (exogenous) or from the liver and other tissues (endogenous).

Triglycerides Characteristics

  • Predominantly derived from plant sources, characterized by high levels of cis polyunsaturated fatty acids, making them liquid at room temperature (e.g., corn, sunflower seeds).

  • Animal-source triglycerides typically contain saturated fatty acids, remain solid at room temperature due to close packing.

Triglycerides Function

  • Classified as neutral lipids, meaning they lack charged groups, making them hydrophobic.

  • Function as:

    • A primary energy source, accounting for 95% of stored fat.

    • Insulation for vital organs through fat deposits in adipose tissue.

Phospholipids

  • The primary lipid form in cell membranes.

    • Comprised of two esterified fatty acids and a phosphate group attached to the third position on a glycerol backbone.

    • Phospholipid types include phosphatidylcholine (lecithin), which is prevalent in lipoproteins and cell membranes.

Phospholipids Properties

  • Known as phosphoglycerides or glycerophosphatides due to their glycerol backbone.

  • Exhibit amphipathic characteristics:

    • Contain both hydrophobic C-H chains and a hydrophilic head group (phosphoric acid), allowing them to orient favorably in lipid bilayers: hydrophilic heads face outward, while fatty acid chains face inward, away from water.

Sphingolipids

  • A lipid class resembling phospholipids, whose backbone is a sphingoid base (e.g., sphingosine) instead of glycerol.

  • Found within brain tissue, cell membranes, and the central nervous system.

Cholesterol

  • A high-molecular weight unsaturated steroid alcohol characterized by four ring structures and a single C-H side chain tail.

  • Cholesterol is amphipathic; its polar hydroxyl group faces outward and can interact with water via hydrogen bonds, while the ring structure and tail remain buried within membranes.

Cholesterol Sources

  • Exogenous sources: obtained from diet including meat, egg yolk, seafood, and whole-fat dairy products.

  • Endogenous sources: synthesized primarily by the liver.

Cholesterol Functions

  • Synthesized in almost all animal tissues from acetyl coenzyme A.

  • Used for:

    • Manufacturing and repairing cell membranes.

    • Synthesizing bile acids and Vitamin D.

    • Facilitating triglyceride transport by lipoproteins.

    • Serving as the precursor for five major classes of steroid hormones (progestogens, glucocorticoids, mineralocorticoids, androgens, and estrogens).

Metabolism of Cholesterol

  • Cholesterol is not metabolized as a source of fuel since it is not readily catabolized by most cells.

Membrane Lipids

  • The three principal types of membrane lipids include phospholipids, glycolipids, and cholesterol.

  • Cell membrane structure comprises layers of lipids, embedded proteins, and carbohydrate chains, forming a lipid bilayer.

Steroids

  • Steroids are categorized along with lipids due to similar solubility characteristics.

  • Biological examples include cholesterol, bile salts, sex hormones, and adrenal cortex hormones.

Lipoproteins

  • Function in lipid transport through the bloodstream, delivering necessary lipids to peripheral cells.

  • Core structure represents the cargo being transported within lipoproteins.

Structure of Lipoproteins

  • Characterized as spherical entities composed of lipids and apolipoproteins.

  • Cholesterol and phospholipids are amphipathic, forming a single monolayer on the surface of the lipoprotein, while triglycerides and cholesteryl esters are neutral/hydrophobic, making up the core region.

  • Apolipoproteins, possessing an amphipathic helix, have hydrophobic amino acids inward and hydrophilic ones facing outward into the aqueous environment.

Roles of Apolipoproteins

  • Functions include:

    • Providing structural integrity to lipoproteins.

    • Maintaining lipid solution during circulation.

    • Directing lipids to target organs and tissues.

    • Acting as ligands for binding to cell-surface receptors.

    • Activating and inhibiting enzymes that modify lipoprotein structure.

Examples of Apolipoproteins

  • apo A-1: predominant protein in HDL.

  • apo B:

    • Major protein in LDL and VLDL;

    • Exists as apo B-100 (found in LDL, VLDL) and apo B-48 (associated with chylomicrons).

  • apo E: in LDL, VLDL, and HDL; acts as a ligand for LDL receptor and chylomicron remnants; plays a role in the transport of cholesteryl esters in plasma and cholesterol redistribution in tissues.

Lipoprotein Structure (continued)

  • Size correlation:

    • Greater lipid content corresponds to larger lipoproteins.

    • Larger lipoproteins have larger cores filled with triglycerides and cholesteryl esters, resulting in a relative density that is lighter due to more lipid content compared to protein.

Major Classes of Plasma Lipoproteins

  • Include:

    • Chylomicrons

    • Very Low-Density Lipoproteins (VLDL) - considered harmful

    • Low-Density Lipoproteins (LDL) - considered harmful

    • Lipoprotein(a)

    • High-Density Lipoproteins (HDL) - considered beneficial.

Chylomicrons

  • Function: Carry dietary triglycerides through the circulatory system to the liver and peripheral cells.

  • Origin: Produced by the intestine by packaging absorbed dietary lipids and proteins.

  • Characteristics:

    • Predominantly composed of triglycerides (90-95% by weight), with lesser amounts of phospholipids (2-6%), cholesteryl esters (2-4%), free cholesterol (1%), and apolipoprotein (1-2% - specifically apo B-48).

Properties of Chylomicrons

  • High size results in scattering light, causing turbidity in postprandial plasma.

  • They float to the surface of plasma stored at 4°C, creating a creamy layer.

  • Clearance from formation of chylomicrons post-meal to liver removal is around 6 hours, leading to absence of chylomicrons in a 12-14 hour fasting specimen.

Clinical Significance of Chylomicrons

  • The presence of a creamy layer in a fasting specimen cooled overnight indicates a clearance defect, potentially linked to issues in lipoprotein lipase production/function.

VLDL (Very Low-Density Lipoproteins)

  • Origin: Produced by the liver.

  • Composition: Enriched in endogenous triglycerides; major apolipoprotein is apo B-100, supplemented by apo E.

  • Function: Transport triglycerides assembled in the liver to peripheral cells for energy or fat storage.

  • Physical properties: Contributes heavily to the turbidity seen in fasting hyperlipidemic plasma, lacking a creamy layer due to smaller, denser structure.

VLDL Composition

  • Composed of approximately:

    • 50-65% triglyceride

    • 8-14% cholesteryl ester

    • 12-16% phospholipid

    • 4-7% free cholesterol

    • 5-10% apolipoprotein.

  • High dietary intake of carbohydrates, saturated, and trans fats can enhance hepatic triglyceride synthesis, resulting in increased VLDL production.

Testing and Clinical Application

  • In individuals with elevated VLDL, serum triglyceride concentrations are significantly increased, producing turbid/lipemic serum.

LDL (Low-Density Lipoproteins)

  • Composition characterized by about 50% cholesterol, making them the richest in cholesterol of the lipoproteins.

  • Synthesis occurs in the liver through the decomposition of VLDL lipoproteins.

  • Role: Transport cholesterol from liver to peripheral tissues, composed mostly of apo B-100.

LDL Characteristics and Clinical Significance

  • Considered the most atherogenic lipoprotein due to smaller size compared to VLDL and chylomicrons, allowing infiltration into vessel walls where they can undergo oxidation and be taken up by macrophages, forming foam cells which are connected to fatty streaks, precursors of plaques.

  • Composition includes:

    • 35-45% cholesteryl esters

    • 6-15% free cholesterol

    • 22-28% phospholipid

    • 4% triglyceride

    • 22-26% apolipoprotein.

  • Increased serum LDL-C levels pose a significant CHD risk factor with eight recognized subclasses, where small, dense LDLs exhibit more proatherogenic behavior.

Lipoprotein(a)

  • Resembles LDL particles but contains apo (a) attached to apo B-100.

  • It may interfere with plasminogen, inhibiting clot resolution and contributing to myocardial infarction (MI) and stroke risk.

HDL (High-Density Lipoproteins)

  • Defined as the smallest and most dense lipoprotein, produced by both the liver and intestine.

  • Usually carries about 20-30% of the total plasma cholesterol, with apo A-1 serving as the major apolipoprotein.

Functions of HDL

  • Engaged in reverse cholesterol transport by removing excess cholesterol from peripheral cells back to the liver to promote excretion or reutilization, acting as an anti-atherogenic factor.

  • The particles consist of approximately:

    • 25-30% phospholipid

    • 15-20% cholesteryl esters

    • 5% free cholesterol

    • 3% triglyceride

    • 45-59% apolipoprotein.

Lipoprotein X

  • An abnormal lipoprotein observed in conditions such as biliary cirrhosis, biliary cholestasis, or mutations in lecithin: cholesterol acyltransferase (LCAT).

  • Characteristically composed of 90% phospholipids and cholesterol, with 10% albumin and apo C, and removed by reticuloendothelial cells in the liver, spleen, and kidneys.

Lipoprotein Physiology and Metabolism

  • Encompasses absorption, exogenous and endogenous pathways reliant on apo-B containing lipoprotein particles.

  • Serve functions that include transporting dietary and hepatic-derived lipids to peripheral cells, releasing fatty acids for energy via lipolysis, and transmitting cholesterol, which may lead to atherosclerosis.

Lipid Digestion

  • Average Western dietary fat intake ranges from 60-130 grams per day.

  • Digestive process involves:

    • Salivary amylase for starch breakdown.

    • Stomach pepsin for protein breakdown.

    • Pancreatic amylase for starch breakdown, while pancreatic lipase cleaves fatty acids from triglycerides in the small intestine.

    • Bile salts and acids from the liver assist in emulsifying dietary fats.

Lipid Breakdown Products

  • Dietary triglycerides convert to monoglycerides, diglycerides, and free fatty acids.

  • Dietary phospholipids are converted into lyso-derivatives (lysophospholipids), and cholesteryl esters change into free cholesterol and fatty acids.

Lipid Absorption

  • More than 90% of dietary triglycerides are absorbed from the intestines, whereas approximately 50% of dietary cholesterol is absorbed.

Circulation and Lipoprotein Interaction

  • Chylomicrons interact with proteoglycans on capillaries, promoting lipoprotein lipase (LPL) binding to hydrolyze triglycerides into free fatty acids and glycerol, which are absorbed by cells for energy.

  • Remnants of chylomicrons transit to HDL and subsequently to the liver with excess fatty acids reconverted into triglycerides for storage.

Exogenous Pathway - Lipase Activity

  • In the event of insufficient carbohydrate energy, hormone-sensitive lipase from adipocytes releases free fatty acids from triglyceride reserves, whereas hormones like epinephrine and cortisol stimulate triglyceride breakdown in adipocytes when glucose is depleted.

  • Insulin counteracts lipolysis in adipocytes and promotes fat storage and glucose utilization.

Liver Processing of Chylomicrons

  • Chylomicron remnants are enzymatically transformed in the liver to free fatty acids, free cholesterol, and amino acids.

  • Cholesterol is partially converted to bile acids for excretion alongside free cholesterol into bile and then the intestine.

Endogenous Pathway

  • Responsible for transport of endogenous hepatic lipids (cholesterol and triglycerides) via VLDL and LDL to peripheral tissues.

VLDL in Endogenous Pathway

  • In the liver, triglycerides are incorporated into VLDL derived from the recirculation of dietary fats and some synthesized directly from dietary carbohydrates.

  • Released into circulation where LPL facilitates breakdown leading to VLDL remnants.

LDL in Endogenous Pathway

  • LDL's primary function revolves around cholesterol transport to peripheral cells via receptor-mediated endocytosis, annotated by interactions with LDL receptors leading to lysosomal degradation.

  • Excess cholesterol can either be converted to neutral cholesteryl esters for storage or utilized for membrane synthesis, regulated by downregulation of enzymes in the cholesterol synthesis pathway and LDL receptors.

Impacts of Abnormalities in LDL Receptor Function

  • Familial hypercholesterolemia (heterozygous) occurs at a frequency of 1 in 500, presenting with half the average LDL receptor levels, leading to diminished hepatic uptake and resulting hypercholesterolemia and premature atherosclerosis, with associated CHD risk by mid-adulthood.

Reverse Cholesterol Transport Pathway

  • HDL assists in maintaining equilibrium of cholesterol by functioning cooperatively with the liver to remove cholesterol from peripheral cells back to the liver for eventual excretion as bile acids/free cholesterol.

  • Two primary routes exist for returning cholesterol to the liver, either directly or via LDL receptors after conversion to LDL via CETP.

Genetic Defects and Hyperlipidemia

  • Various genetic abnormalities predispose individuals to heightened atherosclerosis risk due to impaired cholesterol pathways.

Lipoproteins Analogous to Industry Transport

  • Chylomicrons are likened to large oil tankers carrying dietary triglycerides throughout the circulatory landscape, delivering remnants to the liver.

  • VLDL behaves like tanker trucks transporting triglycerides into cells for energy storage.

  • LDL operates as an empty tanker delivering cholesterol to peripheral cells, while HDL functions as a cleanup crew for excess cholesterol returning it to the liver.

Hormonal Effects on Lipids

  • Insulin: Prevents adipose lipolysis, encouraging fat storage and glucose utilization. Insulin resistance (e.g., Type 2 diabetes) can lead to increased plasma triglycerides and LDL production.

  • Growth Hormone: Stimulates lipolysis and diminishes adipocyte uptake of circulating lipids. GH therapies can restore dyslipidemia in deficient patients.

  • Sex Hormones: Women typically display higher HDL levels and lower total cholesterol/triglycerides than men; this reverses post-menopause as estrogen levels decline.

  • Thyroid Hormone: Serves as a primary metabolic rate regulator; hypothyroidism leads to elevated plasma cholesterol and LDL levels.

Lipid and Lipoprotein Levels Across Populations

  • Women (pre-menopausal): Exhibit greater HDL levels than men, remaining stable after menopause, while also having lower overall cholesterol and triglycerides.

  • Men and Post-menopausal Women: Present higher total cholesterol, LDL cholesterol, and triglycerides, which increase with age.

  • Children: Display lower total cholesterol, LDL, and triglycerides compared to adults, with HDL levels comparable to adult women until puberty.

Lipid Disorders/Dyslipidemias

  • Dyslipidemias arise from genetic abnormalities in lipid synthesis/removal, environmental factors (diet, lifestyle), or as secondary issues linked to diseases (diabetes, hypertension).

  • Defined clinically and through laboratory results, with many associated with a heightened risk of CHD or arteriosclerosis.

Risk Factors for Coronary Heart Disease (NCEP)

  • Positive Risk Factors include:

    • Age (≥ 45 years for men; ≥ 55 years for women).

    • Family history of premature CHD.

    • Cigarette smoking.

    • Hypertension (≥ 140/90 mmHg or antihypertensive medication usage).

    • Elevated LDL-C levels based on risk factor presence.

    • HDL-C levels < 40 mg/dL considered a risk.

    • Diagnosed diabetes mellitus as a CHD equivalent.

  • Negative Risk Factor:

    • HDL-C levels ≥ 60 mg/dL deemed beneficial.

Arteriosclerosis

  • Identified as a leading cause of mortality and disability in developed nations, with an equivalent prevalence in women and men, though women generally develop it a decade later.

  • Contributing factors includes genetic defects related to proteins associated with cholesterol metabolism as well as unfavorable lifestyle choices.

Mechanisms of Arteriosclerosis and Coronary Heart Disease

  • Arterial lipids, predominantly esterified cholesterol, deposit in arterial walls through a series of stages:

    1. Fatty streaks form via lipid accumulation in macrophages within the sub-endothelial space.

    2. Cycles of cellular injury and repair lead to plaque development, which consists of smooth muscle cells, extracellular lipids, calcification, and fibrous tissues.

Role of LDL Cholesterol

  • Suggests that LDL initiates and promotes plaque formation by altering gene expression in cells upon oxidation, leading to inflammation and recruitment of further inflammatory cells, ultimately contributing to vascular narrowing and elevating blood pressure, which exacerbates plaque development.

Myocardial Infarction

  • Occurs when plaque becomes unstable, leading to erosion/rupture which causes hemorrhage, creating a thrombus that obstructs blood flow, provoking ischemia and the risk of sudden heart attacks.

Locations of Plaque Development

  • Can manifest as:

    • Coronary artery diseases (for heart).

    • Cerebrovascular diseases (for brain, causing strokes).

    • Peripheral vascular disease affecting arms/legs, as well as various other organs like the liver and kidneys.

Relationship of Lipids in Arterial Walls

  • The deposits correlate with increased serum LDL cholesterol and decreased HDL cholesterol; minimizing LDL levels is pivotal for lowering CHD risk.

  • It is estimated that a 1% reduction in LDL cholesterol leads to a 2% decline in arteriosclerosis risk, with a threshold less than 2.6 mmol/L being favorable for heart disease patients.

Treatment of Arteriosclerosis

  • Monitoring of lipids and lipoproteins is crucial for clinical management (total cholesterol, HDL, LDL, triglycerides).

  • Treatment guidelines may involve:

    • Dietary changes (low-fat, high-fiber diets).

    • Drug therapies including:

    • Bile acid sequestrants

    • Statins to obstruct cholesterol synthesis

    • Niacin to reduce LDL and augment HDL

    • Fibric acid derivatives to decrease triglycerides and enhance HDL levels.

Factors Influencing HDL Levels

  • Increase HDL through:

    • Niacin, fibric acids, fish oil, estrogen therapy, anti-epileptic medication, intense physical fitness, and moderate alcohol consumption.

  • Decrease HDL via heavy smoking and physical inactivity.

Lipid Disorders: Hyperlipoproteinemia

  • Hypercholesterolemia: Closely linked with heart diseases, including familial hypercholesterolemia.

    • Homozygotes typically experience heart attacks in their teenage years, while heterozygotes face risk by 20-50 years.

    • Results from a buildup of LDL due to defective receptors leading to increased serum cholesterol despite normal synthesis.

  • Hypertriglyceridemia: Diagnosed when triglyceride levels exceed 2.3 mmol/L, resulting from VLDL handling imbalances.

    • Similarly, dyslipidemia can arise from both genetic and secondary causative factors such as diabetes or renal issues.

  • Severity of triglyceride elevation could result in pancreatitis.

  • Treatments include dietary interventions (e.g., fish oil) and pharmacological approaches.

Lipid Disorders: Combined Hyperlipoproteinemia

  • Associated with increased risks for CHD due to lipoprotein(a) levels being augmented, linked to the presence of an additional apolipoprotein, leading to higher cardiovascular risks with potential interventions include niacin or estrogen for women.

Lipid Disorders: Hypolipoproteinemia

  • Hypoalphalipoproteinemia: Characterized by decreased circulating HDL levels (<1.0 mmol/L) without increased triglycerides, raising the probability of premature CHD.

  • Hypobetalipoproteinemia: Defined by diminished LDL levels lacking CHD association.

Preventive Measures for Heart Disease

  • A healthy diet emphasizing fruits, vegetables, and grains can lower LDL levels effectively compared to diets high in animal fats.

    • Recommendations include lower saturated fat and cholesterol intakes for overall health.

  • Consistent exercise and abstinence from smoking are critical.

  • Management of comorbid conditions such as diabetes and hypothyroidism enhances cardiovascular health.

  • Routine lipid profile assessment for all adults is recommended every five years, focusing on total cholesterol, HDL, LDL, and triglyceride metrics, leading to proactive treatment for abnormal results.

References

  • Clinical Chemistry: Principles, Techniques and Correlations. 8th Edition. Bishop, M.L.; Fody, E.P.; Schoeff, L.E. Wolters Kluwer 2018.

  • Tietz: Fundamentals of Clinical Chemistry. 6th Edition. Burtis, C.A.; Ashwood, E.R.; Bruns, D.E.. Saunders Elsevier. 2008.