Lipid Metabolism and Atherosclerosis

Lipid Metabolism: Exogenous Pathway

  • Dietary lipids are converted into chylomicrons.

  • Chylomicrons enter the lymphatic capillaries (lacteals) and then the blood capillaries.

  • Chylomicrons transport lipids to muscle and adipose tissue.

  • Lipoprotein lipase (LPL) breaks down chylomicrons, releasing free fatty acids (FFAs) for uptake by tissues.

  • Chylomicron remnants are taken up by the liver via LDL receptors on hepatocytes.

  • The liver processes these remnants, producing bile acids and cholesterol.

Lipid Metabolism: Endogenous Pathway

  • The liver synthesizes VLDL (very low-density lipoprotein).

  • VLDL is released into the blood capillaries.

  • LPL breaks down VLDL, releasing fatty acids for uptake by muscle and adipose tissue.

  • VLDL remnants become IDL (intermediate-density lipoprotein).

  • IDL has two possible fates:

    • It can be taken back up by the liver.

    • It can be converted into LDL (low-density lipoprotein).

  • LDL can deliver cholesterol to peripheral tissues or return to the liver.

Micelles and Chylomicron Formation

  • Micelles are absorbed in the intestinal brush border.

  • Fatty acids are re-esterified and combined with apolipoprotein B48 (apo B48) to form chylomicrons.

  • Chylomicrons enter the portal circulation, carrying lipids and other absorbed substances to the liver.

VLDL and LDL Pathways

  • VLDL, similar to chylomicrons in the endogenous pathway, transports hepatic lipoproteins to peripheral tissues via LDL.

  • VLDL acquires different apolipoproteins.

HDL's Role in Reverse Cholesterol Transport

  • HDL (high-density lipoprotein) interacts with VLDL to facilitate reverse cholesterol transport, sending cholesterol back to the liver.

  • This process involves cholesterol transfer from HDL to VLDL.

  • HDL is considered "good cholesterol" because it removes cholesterol from circulation and tissues.

  • Following hydrolysis, up to 40% of VLDL IDL becomes LDL and is taken up by the liver via APOE-mediated transfer.

Exogenous vs. Endogenous Lipid Transport

  • Exogenous: Dietary cholesterol is absorbed in the intestine, forming chylomicrons with apo B48.

  • Endogenous: The liver synthesizes VLDL with various apolipoproteins.

  • Lipoprotein lipase (LPL) breaks down chylomicrons and VLDL, releasing cholesterol to different tissues.

  • Chylomicron remnants (with apo B48) are taken up by the liver.

  • VLDL remnants become IDL, which is converted to LDL.

LDL as "Bad Cholesterol"

  • LDL can circulate and deliver cholesterol to extrahepatic tissues (muscle, adipose tissue, brain, kidney, adrenal glands).

  • Oxidized LDL is taken up by macrophages, forming foam cells.

  • HDL can retrieve cholesterol from extrahepatic tissues and transport it back to the liver, either directly or via VLDL and IDL.

Conditions Accelerating Atherosclerosis

  • Gender:

    • Males and females after menopause are at higher risk.

    • Estrogen has an LDL-lowering effect, which is lost after menopause.

    • Estrogen may increase the number of LDL receptors in the liver.

  • Primary Hyperlipidemia:

    • Inherited disorders can cause lipoprotein lipase deficiency (Type 1).

    • Defective LDL receptors (Type 2a) prevent cholesterol uptake by the liver.

    • Other abnormalities include abnormal apoprotein E (Type 3) and deficient apoprotein C.

  • Cigarette Smoking:

    • Carbon monoxide may induce hypoxic injury to endothelial cells.

  • Hypertension:

    • Shear stress damages the endothelium.

  • Diabetes Mellitus (Types 1 and 2):

    • Decreased hepatic removal of LDL.

    • Increased glycosylation of collagen increases LDL binding.

  • Obesity (Especially Abdominal Obesity):

    • Adipose tissue releases endocrine factors that alter endothelial function and increase inflammation.

  • Hypothyroidism:

    • Decreased formation of LDL receptors in the liver.

    • Often associated with hyperlipidemia/dyslipidemia.

Lipoproteins in Detail: LDL

  • Apo B100: The main apolipoprotein. LDL\text{LDL}

  • Composition: Contains cholesterol, a little bit of triglycerides.

  • Function: Major cholesterol transporter in humans.

  • Regulation: Internalized via APO B100 binding to LDL receptors on liver cells.

    • APOB100APO B100 is the point of contact for LDL receptors.

  • PCSK9:

    • Product of the PCSK9 gene.

    • Causes LDL receptors to be removed from the plasma membrane and broken down, reducing the number of LDL receptors.

    • Inhibition of PCSK9 increases the number of LDL receptors on the cell surface, promoting cholesterol uptake by the liver.

Cholesterol Synthesis

  • Occurs in the smooth endoplasmic reticulum of liver cells.

  • Requires a specific enzyme to help make cholesterol.

Clinical trials:

  • Indicate a link between lipoprotein a levels and increased risk of myocardial infarction, coronary artery spasm, ischemic stroke, and cardiovascular mortality. Right? Of course, more research is needed.

Lipoproteins in Detail: Lipoprotein(a)

  • An LDL particle with an added apo(a) (small a) attached to apo B.

  • A biomarker linked to cardiovascular disorders (atherosclerosis) and valvular stenosis.

  • Role in thrombosis at arterial plaque, cholesterol deposition, endothelial dysfunction, and vascular calcification.

LDL and HDL Pathways

  • LDL delivers cholesterol to the liver cells by binding to LDL receptors.

  • HDL, containing APO A1, circulates and matures into HDL through the action of lecithin-cholesterol acyltransferase (LCAT).

  • Mature HDL can go directly to the liver or transfer cholesterol to VLDL, which then becomes IDL, LDL, and eventually delivers cholesterol to liver cells.

  • HDL can also transfer cholesterol to chylomicron remnants, which are taken up by the liver.

HDL Metabolism and Reverse Cholesterol Transport

  • HDL is responsible for reverse cholesterol transport, moving cholesterol back to the liver.

  • It inhibits lipoprotein oxidation and maintains endothelial integrity.

  • Synthesized mostly in the liver and small intestine, consisting of APO A1, phospholipids, and cholesterol.

  • APO A1 is crucial for HDL function.

  • LCAT esterifies cholesterol, forming mature HDL containing cholesterol ester, which can be taken up by the liver.

  • Cholesterol and triglycerides can also be transferred from HDL to VLDL and chylomicrons via cholesterol ester transfer protein (CETP).

Atherosclerosis: Fatty Streak Formation

  • Atherosclerosis involves the formation of plaques in blood vessels.

  • The fatty streak is an early lesion with a translucent, yellowish surface under the endothelium.

  • The endothelium is intact over the fatty streak.

  • Fatty streaks contain foam cells filled with cholesterol.

  • Monocytes are activated and cross the endothelium to become macrophages.

  • Macrophages take up oxidized LDL, becoming foam cells.

  • T cells release cytokines, activating macrophages.

  • Cytokines also stimulate smooth muscle cells to proliferate.

Pathogenesis of Fatty Streaks

  • Initial vascular injury triggers fatty streak formation.

  • Monocytes bind to the endothelium, cross the subendothelial space, and become activated tissue macrophages.

  • Macrophages take up oxidized LDL, becoming foam cells.

  • T cells release cytokines, activating macrophages and stimulating smooth muscle cell proliferation.

Smooth Muscle Cell Involvement

  • Cytokines cause smooth muscle cells to proliferate and migrate from the media to the subendothelial space.

  • Smooth muscle cells also take up lipid particles and become foam cells.

  • The proliferation and accumulation of foam cells contribute to the growth of the fatty streak.

Atherosclerosis: Plaque Development

  • Dyslipidemia, particularly elevated LDL, is a major risk factor for atherosclerosis.

  • Elevated LDL contributes to atherogenesis.

  • Oxidized LDL accumulates in macrophages via scavenger receptors.

  • Mediated uptake leads to cellular dysfunction, apoptosis, and necrosis.

  • Foam cells originate from macrophages and smooth muscle cells.

  • Endothelial injury is caused by inflammatory and prothrombotic molecules released by foam cells and direct interaction of oxidized LDL with the cell surface.

Protective Role of HDL

  • HDL has a protective role in atherogenesis.

  • Maintains endothelial function and mediates reverse cholesterol transport via APO A1.

  • Exhibits antioxidant and antithrombotic effects.

Toxic Effects of Oxidized LDL

  • Stimulates the release of proinflammatory cytokines.

  • Affects macrophages and smooth muscle cells.

  • Inhibits nitric oxide production, reducing vasodilation.

  • Stimulates vascular smooth muscle cells to move from the media to the intima and proliferate.

  • Small, dense LDL particles are more atherogenic than larger LDL particles.

Plaque Composition and Development

  • Plaque material contains damaging substances, including ozone, which promotes the formation of ROS (reactive oxygen species).

  • Cholesterol crystals form from necrotized macrophages, stimulating inflammation and recruiting more neutrophils.

  • Aging plaques attract immune system T cells and monocytes, creating a cycle of necrosis and inflammation.

  • Fibrous caps form over aging plaques.

  • Plaques with defective or broken caps are prone to rupture, leading to thrombosis and blocking, as seen in myocardial infarction.