Atherosclerosis and Cholesterol Metabolism

• Initial case study presented is George, a 56-year-old male, Cholesterol 7.7 mmol/l, Triglyceride 3.6 mmol/l, HDL cholesterol 11 mmol/l, Non hdl cholesterol 6.6 mmol/l, Ldl cholesterol 5 mmol/l, GP suggested to be on statins, Feels well, Has well controlled hypertension, Non smoker and not a heavy drinker

Lipids Related to CVD

• Cholesterol

• Triglycerides

• Fatty acids

• Phospholipids

• Fat is a source of energy, therefore the body prefers it as an energy source

Cholesterol Structure

• The basic structure of cholesterol is a sterol nucleus, synthesized from multiple molecules of acetyl co A.
• The nucleus modification with side chains create cholesterol, colic acid (base of bile acids), and steroid hormones.
• Cholesterol is a cell membrane component and a vitamin D precursor, subsequently affecting signal transduction.
• Replacing the OH group makes it an ester, making it entirely hydrophilic, but Cholesterol is amphiphilic (both polar and nonpolar) due to the OH group being polar and the rest nonpolar.
• Every nucleated cell can produce cholesterol via a highly regulated process.

Triglycerides

• A glycerol backbone is linked to fatty acids

• Mammals only produce even numbers of fatty acids

• Triglycerides are completely hydrophobic

• Saturated fats only have single bonds and are solid at room temperature

• Unsaturated fats have one or more double bonds and are liquid at room temperature

• Monounsaturated fats: olive oil

• Polyunsaturated fats: omega-3 and omega-6

• Natural fatty acids always have cis configuration where hydrogens are on the same side causing a bend in the chain.

• Humans cannot make trans fatty acids.

• Trans fatty acids are created through hydrogenation, with hydrogens on opposite sides of the chain.

• Excess intake of SFA and USFA can increase LDL levels, linking to CVD

• Essential fatty acids: The body can’t synthesize but are required for normal physiological functions

• Alpha-linolenic acid (omega-3) converts into EPA and DHA

• Eicosapentaenoic acid EPA (omega-3) is found in fish and seafood and is important for anti-inflammatory processes and cell membrane fluidity.

• Docosahexaenoic acid DHA, also in fish and seafood, is essential for brain development, retina function, and neuronal membrane

• Arachidonic acid (omega-6) converts to PGs, thromboxanes, and leukotrienes involved in inflammation, immune response, and blood clotting.

• Balance between omega-3 and omega-6 is important

• Omega-3 (EPA & DHA) has anti-inflammatory effects

• Omega-6 (AA) has pro-inflammatory properties

• Excess omega-6 from processed food can cause chronic inflammation

• Triglycerides are nonpolar and can be stored in adipocytes

Phospholipids

• Composed of a hydrophilic head (glycerol backbone and a phosphate group) and a hydrophobic tail (two fatty acids)
• The fats need to change shape to travel in our body due to being highly hydrophobic
• They package into ball-like complexes with hydrophobic lipids inside and hydrophilic parts outside
• Inside the ball: Triglycerides, Cholesterol ester, Phospholipid tails, Free cholesterol
• Apolipoproteins identify and direct movement through the body.

Lipid Metabolism

• Core lipids surround the phospholipid monolayer with attached proteins

• Dietary fat, bile acids, and cholesterol enter the exogenous pathway

• Endogenous cholesterol enters the endogenous pathway in the liver

• Chylomicrons and remnants transport dietary cholesterol

• VLDL, IDL, and LDL transport endogenous cholesterol

• Lipoprotein lipase acts in capillaries associated with adipose tissue and muscle

• Bile acids emulsify fats by breaking them into smaller micelles, increasing the surface area for digestion.

• Pancreatic lipase in the intestines hydrolyzes triglycerides, removing two fatty acids and leaving monoacylglycerol (glycerol with one FA) and two free fatty acids.

• Breakdown products (fatty acids, cholesterol, fat-soluble vitamins) combine with bile salts to form micelles

• Micelles transport hydrophobic lipids combine with bile salts in a watery environment

• Micelles deliver contents to the intestinal brush border membrane

• Fatty acids and monoacylglycerols diffuse into enterocytes, while cholesterol and fat-soluble vitamins are absorbed

• Inside enterocytes, fatty acids and monoacylglycerols reform into new triglycerides, and cholesterol esterifies into cholesteryl esters.

• Triglycerides, cholesteryl esters, and fat-soluble vitamins are packaged into chylomicrons to deliver fats for energy, first entering the lymphatic system and then the bloodstream.

• Lipoprotein lipase (LPL) breaks down triglycerides into fatty acids, which are absorbed by tissues

• As triglycerides reduce, chylomicrons become chylomicron remnants and travel to the liver

• The liver produces cholesterol and packages it into VLDL in the endogenous cholesterol transport (VLDL to LDL) pathway

• VLDL, large and mostly containing triglycerides, have tissues extract triglycerides making very low density lipoprotein smaller which forms IDL (intermediate density lipoproteins)

• IDL continues losing triglycerides becoming low density lipoprotein

• LDL is mainly cholesterol and delivers cholesterol by binding to LDL receptors on cells

• LDL has a high cholesterol content

• LDL oxidizes easily, leading to structural abnormalities

• Oxidized LDL cross-links with blood vessel walls, damaging them and triggering an immune response

• Immune cells engulf oxidized LDL, forming foam cells and leading to atherosclerosis plaque

• HDL gathers damaged LDL and cholesterol from the bloodstream and returns it to the liver, where it can be excreted

• Hormone-sensitive lipase, activated by glucagon when energy is needed, breaks down triglycerides into fatty acids inside the adipose tissue, releasing fatty acids into the bloodstream for energy.

  • Chylomicrons deliver dietary fats to tissues
  • VLDL transports liver-made fats which is converted to LDL, which delivers cholesterol
  • It is important to remember that excess LDL (especially oxidised LDL) contributes to atherosclerosis
  • HDL helps remove excess cholesterol, preventing cardiovascular disease
  • Triglycerides are broken down when energy is needed by hormone-sensitive lipase

Classification of lipoproteins

• Chylomicrons and chylomicron remnants

• VLDL

• IDL

• LDL

• HDL

• CVD is linked to cholesterol levels

• Apolipoprotein B (ApoB) is the structural protein of lipoproteins, acts as a scaffold molecule, and provides structural integrity to VLDL, LDL, and IDL

• LDL contains triglycerides and cholesteryl ester inside, with phospholipids and cholesterol on the outside.

• LDL is a metabolic byproduct of tag and fa removal from larger lipoproteins.

• LDL is rich in cholesterol, but it is not an energy source for the tissues

• Cholesterol in LDL synthesis of bile acids and steroid hormones

• LDL must be oxidised first to become atherogenic

• oxLDL triggers inflammation leading to athersclerotic lesions

  • LDL infiltration & oxidation triggers immune response
  • Macrophages engulf oxidised LDL, forming foam cells
  • Chronic inflammation and foam cell death worsen plaque growth
  • Smooth muscle cells try to stabilise the plaque, but inflammation weakens it
  • Plaque rupture leads to thrombus formation or heart attack/stroke
  • HDL prevents LDL oxidation and removes excess cholesterol

• Cholesterol can be absorbed from the intestine majority of it is produced by the liver and can be also by the systemic tissue

• All cells in the human body has the capacity to synthesize chole de novo they do not rely on extracellular delivery of lipoprotein to them though they can use this exogenous source

• More LDL taken by cells = less LDL in the bloodstream

• Less circulating LDL= less cholesterol going back to the liver

• Thereby the liver acts by reducing VLDL production thinking that cells have enough cholesterol

• If the LDL receptors are absent or defective callss cannot take up LDL, which Means that more LDL will be circulating

• The liver assumes cells lack cholesterol, producing more VLDL -> LDL, which in turn increases atherosclerosis risk.

• High blood LDL increases oxidized LDL, -> increased foam cell formation, basis of familial hypercholesterolaemia

• Familial hypercholesterolaemia (FH), is a genetic condition where LDL receptors are defective/missing

Key Concepts Relating to LDL Receptors and Cholesterol

• LDL receptors regulate cholesterol balance

• More LDL uptake by cells results in lower LDL levels

• Less uptake due to receptor deficiency results in higher LDL levels

• The liver misinterprets this and keeps making more VLDL, worsening hypercholesterolaemia

• FH is a genetic disorder where LDL-C accumulates, increasing atherosclerosis and CVD risks

• FH occurs from defects in the LDL receptor pathway, preventing proper clearance of LDL from circulation

• The molecular basis of FH involves defects in LDL receptor function, ApoB protein, or PCSK9 enzyme activity

Types of FH

• LDLR mutation (defective LDL receptors)

• ApoB protein

• LDLR mutations cause defective or absent LDL receptors, leading to LDL-C buildup

• ApoB defects, such as dysfunctional ApoB, impair binding to LDL receptors

• PCSK9 gain-of-function mutation

  • Impairs the binding of LDL-C to LDL receptors
  • Even if LDL receptors are functioning normally, the function of LDL-C cannot be efficiently removed from circulation
  • The buildup of LDL-C in the blood thus increasing atherosclerosis
  • Results in increased LDL receptor degradation, reducing LDL-C removal
  • The consequence of this buildup leads to early-onset cardiovascular disease.
  • FH is a genetic disorder resulting in extremely high LDL levels, leading to early-onset CHD and atherosclerosis.

FH Treatment

• Treatment types include, Statins, PCSK9 inhibitors, Lifestyle modifications, Lipid apheresis

  • Statins: Lower LDL cholesterol levels
  • PCSK9 inhibitors: Prevent LDL receptor degradation
  • Lifestyle modifications: (healthy diet, exercise)
  • Lipid apheresis: Severe cases of HoFH

• Corneal arcus is a grey-white yellowish circle that surrounds the periphery of the cornea due to lipid deposition in the corneal stroma, can be caused by FH in patients under 40

• CVD risk in younger individuals is linked to increased CVD

• Xanthelasma presents as yellowish, soft, raised plaques typically appear around the eyelids, especially the medial canthus and are composed of lipid-laden macrophages

• Hyperlipidemia, often linked to high cholesterol in younger patients, is a CVD risk factor associated with atherosclerosis

• Tendon xanthomas result from the deposition of cholesterol in the tendons

• For someone with homozygous FH, CHD can develop by age 12 without treatment

• Someone with heterozygous FH can develop CHD by age 35

• Those with high cholesterol but without FH can develop heart disease by 55

• Risk of developing CVD increases as the person has higher LDL levels

• In plots of LDL vs CHD risk, the relationship is linear on a log scale; IHD risk starts at 40 mg/dl (1.0 mmol/L)

Treatment Approaches

• Small molecules, monoclonal antibodies, And siRNA act via LDL Receptors
• Small molecules are located intracellularly and extracellularly
• Antibodies are located extracellularlyl
• Gene silencing happens intracellularly (and extracellularly)

Pharmacological treatments for high LDL levels

• Small molecules:
  • statins reduce cholesterol formation and upregulate LDLR expression
  • bempedoic acid
  • ezetimibe inhibits cholesterol uptake in intestines
• PCSK9 inhibition:
  • pcsk9 monoclonal antibodies block pcsk9 from binding to LDLR, preventing LDLR degradation
  • enhancing LDLR availability for LDL uptake and clearance
• Cholesterol depletion mechanism:
  • intracellular cholesterol depletion leads to increased LDLR synthesis, enhancing LDL uptake.

This quiz covers the role of smooth muscle cells and LDL receptors in atherosclerosis. It also covers familial hypercholesterolemia, corneal arcus, and xanthelasma. Test your knowledge of cholesterol metabolism and related conditions.