Metabolism 4.2 Lipid Transport

• Learning Outcomes

  • Describe how lipids are transported in the blood.

  • Explain how tissues obtain lipids from lipoproteins.

  • Explain how lipid transport disturbances lead to clinical problems.

  • Explain how hyperlipoproteinaemia may be treated.

Lipids and Lipoproteins: Fundamental Concepts

• Lipids are hydrophobic molecules

  • Insoluble in water.

• Transport in blood requires carriers

  • Lipoprotein particles carry
    $\sim98\%$
    of lipids.

  • 
    $\sim2\%$
    of fatty acids are bound to albumin (limited capacity).

• Lipoprotein particles composition

  • Composed of phospholipids, cholesterol, cholesterol esters, proteins, and triacylglycerols (TGs).

• Major lipid forms discussed

  • Triacylglycerols (TG), Diacylglycerol (DAG), Monoacylglycerol (MAG), Fatty acids, Cholesterol, Cholesterol esters, Phospholipids, Vitamins A, D, E, K.

Lipoprotein Structure and Components

• Lipoproteins consist of two main regions

  • Polar surface coat (shell): Rich in phospholipids, unesterified cholesterol, and apolipoproteins.

  • Nonpolar lipid core: Contains triacylglycerol and cholesterol esters.

• Apolipoproteins fall into two classes

  • Integral apolipoproteins (e.g., apoA, apoB): Pass through the phospholipid layer.

  • Peripheral apolipoproteins (e.g., apoC, apoE): Loosely bound to the surface.

• Roles of apolipoproteins

  • Structural: Package water-insoluble lipids into soluble forms.

  • Functional: Cofactors for enzymes and ligands for cell-surface receptors.

• Common apolipoprotein classes

  • apoB: Present in chylomicrons, VLDL, IDL, LDL.

  • apoAI: Found in HDL.

  • apoC and apoE: Present in chylomicrons, VLDL, and HDL.

Lipoprotein Classes and Their Basic Properties

• Five distinct classes (named by density)

  • Chylomicron

  • Very Low Density Lipoprotein (VLDL)

  • Intermediate Density Lipoprotein (IDL)

  • Low Density Lipoprotein (LDL)

  • High Density Lipoprotein (HDL)

• Density ranges ($ext{g/ml}$), measured by ultracentrifugation

  • HDL:
    $1.063 ext{ to } 1.21$

  • LDL:
    $1.019 - 1.063$

  • IDL:
    $1.006 - 1.019$

  • VLDL:
    $0.95 - 1.006$

  • Chylomicron:
    <0.95

• Particle diameters (size roughly inversely proportional to density)

  • Chylomicron:
    $100 - 1200 ext{ nm}$

  • VLDL:
    $30 - 80 ext{ nm}$

  • IDL:
    $25 - 30 ext{ nm}$

  • LDL:
    $18 - 28 ext{ nm}$

  • HDL:
    $5 - 15 ext{ nm}$

• Typical approximate composition (Protein, TG, Cholesterol, Cholesterol Ester)

  • Chylomicron: Protein $<br>\sim1\%$
    , TG $<br>\sim88\%$
    , Cholesterol $<br>\sim1\%$
    , CE $<br>\sim3\%$

  • VLDL: Protein $<br>\sim10\%$
    , TG $<br>\sim56\%$
    , Cholesterol $<br>\sim8\%$
    , CE $<br>\sim15\%$

  • IDL: Protein $<br>\sim10\%$
    , TG $<br>\sim29\%$
    , Cholesterol $<br>\sim9\%$
    , CE $<br>\sim39\%$

  • LDL: Protein $<br>\sim20\%$
    , TG $<br>\sim13\%$
    , Cholesterol $<br>\sim6\%$
    , CE $<br>\sim48\%$

  • HDL: Protein $<br>\sim50\%$
    , TG $<br>\sim13\%$
    , Cholesterol $<br>\sim6\%$
    , CE $<br>\sim30\%$

• Main carriers of TGs: Chylomicrons and VLDL.

• Main carriers of cholesterol esters: LDL and HDL.

• Lipoprotein content and density

  • Reflect the relative lipid vs. protein content.

Dietary Fat Trafficking and Overview of Lipoprotein Transport

• Dietary fat and cholesterol absorption

  • Occurs in the small intestine.

• Chylomicron formation and transport

  • Formed in the intestinal mucosa.

  • Transported to the bloodstream via the lymphatic system (small intestine mucosa -> lymphatic vessels -> thoracic duct -> left subclavian vein -> blood).

• In capillary beds

  • Chylomicrons are hydrolyzed by lipoprotein lipase (LPL) to release fatty acids for muscle and adipose tissue.

  • Remnants are cleared by the liver.

• Liver produces VLDL

  • VLDL travels in blood and becomes progressively lipid-depleted (via LPL) to form IDL and then LDL.

• HDL participates in cholesterol transport

  • Picks up cholesterol from peripheral tissues.

  • Transfers it to other lipoproteins (via CETP) or delivers it to the liver via SR-B1 after LCAT action.

Key Enzymes and Processes in Lipoprotein Metabolism

• Lipoprotein lipase (LPL)

  • Localized on capillary walls of muscle and adipose tissue.

  • Hydrolyzes TGs in chylomicrons and VLDL to fatty acids and glycerol.

  • Requires ApoCII as a cofactor.

  • Fatty acids are taken up by tissues for energy or storage; chylomicron/VLDL TG content decreases, forming remnants.

• Endocytosis and receptor interactions

  • LDL receptor binds LDL via apoB-100 and mediates endocytosis into cells.

  • After uptake, cholesterol inhibits de novo synthesis and downregulates LDL receptor expression.

  • Receptor-mediated endocytosis also applies to chylomicron remnants via ApoE interactions with hepatic receptors.

• Lipoprotein remodeling and transfer proteins

  • LCAT (lecithin–cholesterol acyltransferase): Esterifies cholesterol on HDL, generating cholesterol esters that move to the HDL core.

  • CETP (cholesterol ester transfer protein): Transfers cholesteryl esters from HDL to TG-rich lipoproteins (e.g., VLDL) in exchange for TG.

  • ABCA1 (ATP-binding cassette transporter A1): Mediates transfer of cholesterol to lipid-poor APOA1, initiating HDL formation.

  • SR-B1 (scavenger receptor class B type 1): Mediates selective uptake of cholesteryl esters from HDL by the liver.

• Important overall concept

  • HDL participates in reverse cholesterol transport, collecting cholesterol from peripheral tissues and delivering it to the liver for disposal.

Chylomicrons: Formation and Maturation

• Formation

  • Chylomicrons are formed in the small intestine.

• Composition and function

  • Rich in dietary TGs.

  • Carry dietary TGs to peripheral tissues (especially adipose tissue).

• Circulation timing

  • Normally present in blood
    $4-6$
    hours after a meal and are cleared thereafter.

  • Persistence after
    $6$
    hours is clinically problematic.

• Appearance

  • Milky (lipemic) plasma when abundant.

• Maturation

  • Nascent chylomicrons acquire apoCII and apoE from HDL in the bloodstream to become mature chylomicrons.

Chylomicron Metabolism: Detailed Steps

• Nascent chylomicrons

  • ApoB-48 is added to chylomicrons in enterocytes.

• Excretion and transport

  • Exocytosed into lymphatics, then to the thoracic duct and into the bloodstream.

• In blood

  • Acquire apoCII and apoE from HDL to become mature chylomicrons.

• Lipolysis in tissues

  • ApoCII activates lipoprotein lipase (LPL) on capillary walls of adipose tissue and muscle.

  • LPL hydrolyzes TGs in chylomicrons to release fatty acids for uptake by tissues.

  • This process depletes chylomicrons of TG content to about
    $\sim20\%$
    remaining.

• Post-lipolysis fate

  • ApoCII is returned to HDL after TG hydrolysis.

  • Remnant chylomicrons (now cholesterol and cholesterol esters rich) are enriched in ApoE and are cleared via receptor-mediated uptake by hepatocytes.

  • In hepatocytes, remnants fuse with lysosomes and contents are degraded to amino acids, free cholesterol, and fatty acids.

• Key role of LPL

  • Enables tissue uptake of fatty acids and generating remnant particles for hepatic clearance.

Very Low Density Lipoprotein (VLDL) Pathway: Formation to LDL

• Hepatic production

  • VLDL is formed in the liver for transporting TGs to other tissues.

• ApoB-100 incorporation

  • ApoB-100 is added to nascent VLDL, which is released directly into the bloodstream.

• Remodeling in blood

  • ApoCII and ApoE are transferred from HDL to VLDL to generate mature VLDL.

  • VLDL binds LPL on muscle and adipose tissue, releasing fatty acids and glycerol to tissues, forming VLDL remnants.

  • Some TGs from VLDL are transferred to HDL; some cholesteryl esters are transferred to VLDL.

• Transition stages

  • When VLDL TG content falls to
    $\sim30\%$
    , the particle becomes a short-lived IDL particle while still TG-rich.

IDL and LDL: Transitions and Fate

• IDL formation

  • As VLDL TGs are removed, the particle becomes IDL.

• IDL fates

  • Either taken up by the liver via ApoE-mediated receptor interactions and processed by hepatic triglyceride lipase (HTGL).

  • Or further processed in the bloodstream to form LDL.

• LDL formation

  • When IDL TGs and ApoCII/ApoE are sufficiently depleted, IDL becomes LDL.

• LDL metabolism

  • LDL transports cholesterol to peripheral tissues.

  • LDL binds to cells expressing LDL receptors via ApoB-100 and is endocytosed.

  • High intracellular cholesterol suppresses de novo cholesterol synthesis and LDL receptor expression, reducing further uptake.

• Clinical implication

  • Defects in LDL receptor function lead to elevated blood cholesterol and increased cardiovascular disease risk.

HDL: Reverse Cholesterol Transport and Goals

• HDL origin and maturation

  • HDL is synthesized in the liver and intestine.

  • Nascent HDL is disc-shaped and initially contains only ApoA-I; ApoCII and ApoE are added during maturation.

  • HDL can also be derived from chylomicrons and VLDL during lipolysis by LPL.

• Maturation process

  • ABCA1 mediates cholesterol efflux to ApoA-I, forming nascent HDL.

  • LCAT esterifies cholesterol (activated by ApoA-I) to form cholesterol esters, which move to HDL core, giving HDL its spherical shape.

  • CETP mediates transfer of cholesterol esters from HDL to TG-rich lipoproteins in exchange for TGs.

• Re-entry of cholesterol to liver

  • HDL delivers cholesteryl esters to the liver via SR-B1; hepatic uptake returns cholesterol to the liver for disposal as bile acids or re-use.

• Functional notes

  • HDL exhibits anti-atherogenic properties beyond transport, including antioxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic effects.

Diagnostic and Clinical Relevance: Lipid Levels and Risk Factors

• Blood lipid measurements (typical reference values)

  • Triacylglycerol:
    $1.0 ext{ mmol/L}$

  • Phospholipids:
    $2.5 ext{ mmol/L}$

  • Total cholesterol:
    $5.0 ext{ mmol/L}$

  • Cholesterol esters:
    $3.5 ext{ mmol/L}$

  • Free fatty acids:
    $0.4 ext{ mmol/L}$

• Diagnostic details

  • LDL-C is a primary target for cardiovascular risk reduction; HDL-C is protective; triglycerides provide additional risk information.

• LDL oxidation and atherogenesis

  • Oxidized LDL is taken up by macrophages, transforming them into foam cells that accumulate in vessel walls, forming fatty streaks and potentially atherosclerotic plaques.

• Lp(a) relevance

  • Lp(a) contributes to pro-adhesion, pro-inflammatory signaling, and may promote plaque instability; interactions include MCP-1, VCAM-1, ICAM-1, selectins, and inflammatory cytokines.

• Atherogenesis cascade (simplified)

  • Raised LDL --> oxidized LDL --> macrophage uptake --> foam cells --> fatty streak --> plaque formation --> potential rupture and thrombosis (stroke, myocardial infarction, angina).

Hyperlipoproteinaemia (Types, Causes, and Clinical Signs)

• Definition and causes

  • Defined by raised levels of one or more lipoprotein classes.

  • Causes include overproduction or under-removal of lipoproteins.

• Defects may involve

  • Enzymes (e.g., LPL), receptors (e.g., LDL receptor), apolipoproteins (e.g., apoE, apoAI).

• Common classification (6 main classes)

  • Type I: Chylomicrons in fasting plasma (rare); no clear link to CAD.

  • Type IIa: Raised LDL; CAD risk increased; due to defective LDL receptor.

  • Type IIb: Raised LDL and VLDL; CAD risk; defect unknown.

  • Type III: Raised IDL and chylomicron remnants; CAD risk; defect in apoE.

  • Type IV: Raised VLDL; CAD risk; defect unknown; overproduction or under-removal.

  • Type V: Raised chylomicrons and VLDL in fasting plasma; CAD risk; undefined defects.

• Clinical signs of hyperlipidaemia (often with elevated cholesterol)

  • Xanthelasma: Lipid deposits around eyelids.

  • Tendon xanthomas: Nodules on tendons.

  • Corneal arcus: White/opaque ring around the cornea.

Diet, Lifestyle, and Pharmacological Treatment Strategies

• Initial management (lifestyle and diet)

  • Reduce dietary cholesterol and saturated fats.

  • Increase dietary fiber.

  • Increase physical activity; stop smoking.

• Pharmacological options (when lifestyle changes are insufficient)

  • Statins (e.g., atorvastatin, simvastatin): Inhibit HMG-CoA reductase, lowering cholesterol synthesis and upregulating LDL receptors.

  • Bile salt/acid sequestrants (e.g., cholestyramine, colestipol): Bind bile acids in the GI tract, reducing cholesterol reabsorption and hepatic cholesterol pool, which upregulates LDL receptors.

• Statins: mechanism in more detail

  • Inhibit HMG-CoA reductase in the cholesterol biosynthesis pathway, reducing mevalonate production and endogenous cholesterol synthesis.

  • Result: increased hepatic LDL receptor expression, enhancing clearance of circulating LDL-C.

  • Potential side consideration: decreased synthesis of Coenzyme Q10 (related mitochondrial/protein synthesis effects) with some statins.

Practical Notes on Cholesterol Transport and Clinical Interpretation

• Cholesterol transport and risk markers

  • Total cholesterol (TC) and LDL-C: Traditional risk markers; high TC/LDL-C associated with increased cardiovascular risk.

  • Non-HDL cholesterol (non-HDL-C): Calculated as TC minus HDL-C; target typically
    $\le 4.0 ext{ mmol/L}$
    .

  • TC:HDL-C ratio: Risk indicator; ratio
    >6
    is considered high risk.

  • Triglycerides (TG): Ideally
    <2.0 ext{ mmol/L}
    in a fasted sample.

• HDL and reverse cholesterol transport

  • Role in reducing vascular risk via cholesterol clearance to the liver.

Summary of Lipoprotein Functions (At-a-Glance)

• Chylomicrons: Transport dietary TG from intestine to tissues (mainly adipose tissue).

• VLDL: Transport TG synthesized in liver to adipose tissue for storage.

• IDL: Short-lived precursor of LDL; transports cholesterol synthesized in liver to tissues.

• LDL: Main carrier of cholesterol to tissues; derived from VLDL/IDL.

• HDL: Transports excess cholesterol from cells to liver for disposal as bile acids and to cells requiring cholesterol; exhibits protective properties.

Quick Clinical Correlations and Take-Home Messages

• Lipoprotein metabolism is a coordinated process

  • Involving production, remodeling, and clearance via enzymatic actions and receptor-mediated uptake.

• Disturbances in any step

  • (Enzyme function, receptor activity, or apoprotein composition) can lead to hyperlipoproteinaemia and increased atherosclerotic risk.

• Management typically starts with diet and lifestyle

  • Statins are often first-line pharmacotherapy; additional agents (e.g., bile acid sequestrants) are used when necessary.

• Understanding the lipoprotein spectrum

  • (Chylomicrons, VLDL, IDL, LDL, HDL) helps interpret lipid panels and individual risk in clinical practice.

References to Exam-Style Topics (Core Ideas to Remember)

• Lipoprotein classes, their density, and composition.

• Role of ApoB-100 in LDL and VLDL; ApoB-48 in chylomicrons.

• ApoCII as cofactor for LPL; ApoE for hepatic remnant clearance.

• Enzymes: LPL, HTGL; LCAT; CETP; ABCA1; SR-B1.

• Key clinical links: Atherosclerosis, oxidized LDL, foam cells, Lp(a), and signs like xanthelasma and corneal arcus.

• Treatments: Statins (HMG-CoA reductase inhibitors) and bile salt sequestrants; lifestyle measures.