Lipoproteins and Their Metabolism

Lipoproteins, Metabolism & Diseases

• The presentation covers lipoproteins, their metabolism, and related diseases.
• The date of the presentation is October 10-11, 2024.

Classification of Lipoproteins

• Four systems (methods) are used to isolate, separate, and characterize lipoproteins:

  • Analytical centrifugation
  • Preparative centrifugation
  • Electrophoresis
  • Precipitation techniques

• Different lipoproteins (chylomicrons, VLDL, LDL, HDL) are separated based on density and electrophoretic mobility.

Lipoprotein Structure

• Lipoproteins are spherical structures with a hydrophobic core (triglycerides and cholesterol esters) surrounded by a phospholipid and protein layer.
• Key components include free cholesterol, phospholipids, cholesterol esters, triglycerides, and apolipoproteins (proteins).

Chylomicrons

• Chylomicrons primarily transport dietary triglycerides.

• They are composed primarily of triglycerides, combined with cholesterol, phospholipids, and specific apoproteins (apo B-48, A-I, A-II, C-I, C-II, C-III, a small amount of apo B-100, E-II, E-III, and E-IV).

• Chylomicrons are absent in healthy individuals after 10-12 hours post-meal.

Very Low-Density Lipoproteins (VLDL)

• Average VLDL contains 52% triglycerides, 18% phospholipids, 22% cholesterol, and 8% protein.
• The proportion of triglycerides (TG) and apo-C in a VLDL particle increases with particle size, while the proportion of other components like phospholipids (PL), apo-B, and other apoproteins decreases.
• Partially degraded VLDL (remnants) are rich in cholesterol and are considered highly atherogenic.

Low-Density Lipoproteins (LDL)

• LDL is primarily composed of 80% lipid and 20% protein.
• Approximately 50% of LDL's lipid is cholesterol.
• LDL constitutes a significant portion (40-50%) of plasma lipoprotein mass in humans.
• LDL is the primary carrier of cholesterol and is associated with atherosclerotic conditions.

High-Density Lipoproteins (HDL)

• HDL is composed of 50% protein and 50% lipids.
• HDL is the smallest and densest lipoprotein (density 1.063-1.21).
• HDL's most important lipid is phospholipid, though cholesterol is also of interest.
• Phosphatidylcholine (lecithin) accounts for a majority (70-80%) of HDL's total phospholipids.

Lipoprotein Metabolism

• Lipoprotein transport systems transport hydrophobic core lipids (triglycerides and cholesterol esters).
• Circulating lipoproteins are continuously modified by enzymes and proteins in the metabolic cascade.
• Lipoprotein metabolism involves three pathways (exogenous, endogenous, and reverse cholesterol transport).

Exogenous Pathway

• The exogenous pathway transports dietary fat to peripheral tissues.

Endogenous Pathway

• This pathway transports hepatically synthesized lipids, primarily VLDL triglycerides, to the utilization sites in peripheral tissue.
• In peripheral circulation, chylomicrons and VLDL share a common metabolic pathway catalyzed by lipoprotein lipase (LPL).

Reverse Cholesterol Transport

• The metabolic end products of the lipolytic process clear from plasma by hepatic receptor-mediated processes.
• Reverse cholesterol transport shuttles cholesterol from peripheral tissues to the liver, primarily using HDL, but also some other endogenous derived lipoproteins (e.g., VLDL, LDL).

Chylomicrons (Continued)

• Chylomicrons are produced exclusively in the intestine and travel through the lymphatic system to the thoracic duct before entering systemic circulation.
• The primary function of chylomicrons is the transport of dietary triglycerides.
• Newly made chylomicrons absorb apoC-II from HDL before entering circulation.
• Hydrolysis of chylomicrons yields free fatty acids (NEFAs) and monoglycerides; the result is a chylomicron remnant particle.

Intermediate Density Lipoprotein (IDL)

• IDL is a transient lipoprotein often present in low concentrations in fasting individuals.
• The removal of triglycerides from IDL leaves a particle with primarily cholesteryl esters and apoB, transforming it into LDL.

Low-Density Lipoprotein (LDL)

• In a healthy person, LDL cholesterol makes up about two-thirds of total plasma cholesterol.
• LDL transports cholesterol to hepatic and extrahepatic tissues where it's used, deposited, and excreted.
• LDL is taken up by peripheral tissues and degraded by lysosomes to create free cholesterol.
• Excess intracellular cholesterol leads to cholesterol ester storage.
• Internalization of LDL reduces the available receptors.

High-Density Lipoprotein (HDL)

• Liver and intestines produce lipid-poor apoA-1, which interacts with ABCA1 on arterial macrophages.
• This process transports free cholesterol to lipid-poor HDL.
• Deficiency in this protein can lead to cholesterol accumulation in peripheral tissues.

ApoE

• ApoE is a significant component of nascent HDL, while mature HDL predominantly contains apoA with minor amounts of apoC and E.
• HDL balances LDL transport by removing cholesterol from peripheral sites to degradative/excretory sites; this role is vital for protecting against cardiovascular disease (CVD).

SR-B1

• SR-B1, a scavenger receptor class B type 1, is a membrane receptor that facilitates the uptake of HDL-derived cholesteryl esters into cells and tissues.
• SR-B1 also promotes cholesterol efflux from peripheral tissues (like macrophages) back to the liver.

Pathological Conditions

Hyperlipidemia

• Hyperlipidemia refers to elevated plasma lipids (total cholesterol, free cholesterol + cholesterol ester, and triglyceride).
• Hyperlipidemia might be asymptomatic but can contribute to atherosclerosis, a factor in CVD development if present for a prolonged period.

Hyperlipoproteinemia

• Hyperlipoproteinemia is elevated serum lipoprotein concentrations.
• Classification begins with the identification of abnormal lipoprotein profiles.
• Further analysis is necessary, including: separating hyperlipoproteinemias into primary and secondary forms; further differentiating primary forms (heritable, non-heritable); and determining relative lipoprotein concentrations (VLDL, LDL, and HDL cholesterol).
• Many types of hyperlipoproteinemia exist, but heritable hyperlipidemias commonly present six types of abnormal lipoprotein patterns.

Metabolic Syndrome

• The National Cholesterol Education Program (NCEP) ATP III defines Metabolic Syndrome (MS) as a cluster of interrelated metabolic risk factors tied to atherosclerotic cardiovascular disease (CVD) development.
• MS is significantly associated with a generalized metabolic disorder, insulin resistance, and impaired insulin action.

Coronary Artery Disease (CAD)

• CAD results primarily from atherosclerosis, currently understood as an inflammatory process.
• Atherosclerosis occurs via accumulation of fatty deposits in coronary artery walls, resulting in fibrous tissue formation.
• CAD commonly leads to cardiovascular issues and is one of the leading causes of death globally.

Risk Factors for Coronary Artery Disease (CAD)

• CAD risk factors can be categorized into non-modifiable (age, gender, family history, ethnicity, genetic factors, previous CAD) and modifiable (blood pressure, total cholesterol, HDL cholesterol, smoking, blood sugar, BMI, markers of chronic inflammation), along with lifestyle and social factors (smoking, diet, exercise, stress, income, social deprivation, and environment).

Changes in Analyte in Disease

• The NCEP ATP III study aimed to standardize approaches for detecting and classifying high-risk individuals for coronary heart disease (CHD) and standardizing their treatment and monitoring.

Guideline Recommendations for Lipid Management

• The guideline recommends complete lipoprotein profiling (total, LDL, HDL cholesterol, and triglycerides) as an initial test.
• LDL cholesterol <100 mg/dL is considered optimal.
• Low HDL cholesterol is <40 mg/dL.
• Triglycerides <150 mg/dL are normal.
• Therapeutic goals based on the number of risk factors: zero or one risk factor <160 mg/dL; two or more risk factors <130 mg/dL; and CHD and CHD risk equivalents <100 mg/dL.

ATP III Classification of Cholesterol Concentrations

This quiz explores the structure, classification, and metabolism of lipoproteins as well as associated diseases. Learn about the different types of lipoproteins, their isolation methods, and their roles in health and disease. Perfect for those studying biochemistry or related fields.