Metabolismo de Lipoproteínas

Key Concepts

• Lipoproteins: Spherical macromolecules that transport lipids (triglycerides and cholesteryl esters) through the bloodstream.
• Apolipoproteins: Proteins on the surface of lipoproteins that maintain structure and act as labels for lipid loading/unloading and enzyme activation (Apo-A1, ApoB-48, ApoB-100, ApoC-2, ApoE).
• Exogenous Pathway: Transports dietary lipids from the intestine to tissues, including the liver, using chylomicrons.
• Endogenous Pathway: Transports lipids from the liver to extrahepatic tissues using VLDL, IDL, and LDL.
• Reverse Pathway: Transports lipids from extrahepatic tissues back to the liver for excretion, using HDL.
• LPL (Lipoprotein Lipase): Enzyme that hydrolyzes triglycerides in lipoproteins, releasing fatty acids for tissue uptake.
• LCAT (Lecithin Cholesterol Acyl Transferase): Enzyme that esterifies cholesterol in HDL, enabling it to become spherical.
• CETP (Cholesteryl Ester Transfer Protein): Plasma protein that exchanges cholesterol esters between HDL and other lipoproteins.

1. Introduction to Lipoproteins and Apolipoproteins

• Lipids are insoluble in water, requiring lipoproteins for transport in the bloodstream.
• Lipoproteins are spherical macromolecules with a phospholipid and cholesterol monolayer and a core of triglycerides and cholesteryl esters.
• Apolipoproteins maintain lipoprotein structure and act as signals for lipid metabolism. Key apolipoproteins include Apo-A1, ApoB-48, ApoB-100, ApoC-2, and ApoE.
• "The name of each apolipoprotein is given by the prefix "Apo-" followed by a letter."

2. Lipid Transport Pathways

• Three main pathways: exogenous, endogenous, and reverse.
• Each pathway uses specific lipoproteins that change in size and density as they distribute lipids.
• Lipoproteins generally start large and loaded with lipids, becoming smaller and denser as they deliver their cargo.

3. Exogenous Pathway: Dietary Lipid Transport

• Transports "exogenous" lipids from the diet, starting in the small intestine.
• Digestion of lipids involves bile salts, which are amphipathic molecules that emulsify lipids for enzyme action.
• Pancreatic lipase digests triglycerides into fatty acids, diacylglycerol, and monoacylglycerol.
• Cholesteryl esterase hydrolyzes cholesteryl esters into free cholesterol and fatty acids.
• Enterocytes (intestinal cells) take up these smaller molecules and rebuild triglycerides and cholesteryl esters.
• Triglycerides are synthesized via the monoacylglycerol pathway (using monoacylglycerol and acyl-transferase enzymes) or the phosphatidic acid pathway (using glycerol-3-phosphate).
• Cholesteryl esters are synthesized by ACAT (acyl-CoA: cholesterol acyl-transferase), which binds a fatty acid to free cholesterol.
• Enterocytes package triglycerides and cholesteryl esters into chylomicrons, which are released into the lymphatic system (lacteal duct).
• Newly synthesized chylomicrons contain ApoA-1 and ApoB-48. ApoB-48 serves as a unique marker for chylomicrons.
• In the blood, chylomicrons receive ApoC-2 and ApoE from HDL and transfer ApoA-1 to HDL.
• ApoC-2 activates LPL (lipoprotein lipase) on the endothelium of blood vessels.
• LPL hydrolyzes triglycerides in chylomicrons, releasing fatty acids that are taken up by muscle cells (for energy) and adipose tissue (for storage as triglycerides).
• After delivering triglycerides, chylomicrons become "remnant chylomicrons," containing ApoB-48, ApoE, and cholesteryl esters.
• Hepatocytes (liver cells) take up remnant chylomicrons via LRP receptors, heparin sulfate proteoglycans, and LDL receptors (binding ApoB-48 and ApoE).
• The liver uses the cholesteryl esters to synthesize bile salts.
• Insulin regulates the exogenous pathway by increasing LPL activity and promoting glucose uptake in adipocytes for triglyceride synthesis. Insulin promotes energy storage.

4. Endogenous Pathway: Liver-Derived Lipid Transport

• Transports "endogenous" lipids from the liver to extrahepatic tissues.
• Hepatocytes package triglycerides and cholesterol into VLDL (very-low-density lipoprotein) with ApoB-100.
• VLDLs receive ApoC-2 and ApoE from HDL in the circulation.
• ApoC-2 activates endothelial LPL, which hydrolyzes triglycerides in VLDLs, releasing fatty acids.
• After losing triglycerides, VLDLs become IDL (intermediate-density lipoprotein), richer in cholesterol and lacking ApoC-2.
• IDLs are either taken up by hepatocytes via LDL receptors (binding ApoB-100 and ApoE) or processed by hepatic lipase.
• Hepatic lipase releases fatty acids from IDL, converting them into LDL (low-density lipoprotein), which is rich in cholesteryl esters and contains only ApoB-100.
• LDLs have a long half-life (3 days) and are endocytosed by various tissues via LDL receptors (binding ApoB-100).
• Tissues that actively use cholesterol for biosynthesis (liver, adrenal glands, ovaries, oligodendrocytes) are primary destinations for LDL uptake.
• Intracellular cholesterol levels regulate LDL uptake via the SREBP2, SCAP, and INSIG system.
  • Low cholesterol: SREBP2 and SCAP migrate to the Golgi, where SREBP2 is cleaved and activates transcription of LDL receptor genes.
  • High cholesterol: Cholesterol retains SREBP2, SCAP, and INSIG in the endoplasmic reticulum, inhibiting LDL receptor synthesis.
• Excess free cholesterol promotes its own storage by increasing ACAT activity, leading to the formation of cholesterol esters.
• If LDL levels are too high, LDL can become oxidized (oxLDL).
• Macrophages near vessels (subendothelial macrophages) capture and phagocytose oxLDL via scavenger receptors.
• In hypercholesterolemia, macrophages take up excessive amounts of cholesterol, leading to atheroma plaque formation and atherosclerosis. Scavenger receptors are not regulated by product feedback.

5. Reverse Pathway: Cholesterol Removal

• Transports lipids from extrahepatic tissues back to the liver for excretion.
• HDL (high-density lipoprotein) is synthesized by the liver and intestine.
• HDL goes through four stages: ApoA-1, pre-β-HDL, HDL3, and HDL2.
• ApoA-1 is released into circulation and collects cholesterol from extrahepatic tissues via ABCA1 and ABCG1 proteins (ATP-dependent cholesterol exporters).
• As ApoA-1 accumulates cholesterol and phospholipids, it becomes nascent HDL (pre-beta-HDL or discoidal HDL).
• LCAT (lecithin cholesterol acyl transferase) esterifies cholesterol in HDL, making it more hydrophobic and causing it to move into the core of the lipoprotein.
• LCAT transforms discoidal HDL into HDL3 and then HDL2 (spherical HDL or alpha-HDL).
• HDL2 delivers cholesterol to the liver directly (via SR-B1 receptors) or indirectly (via CETP).
• CETP exchanges cholesterol esters from HDL for triglycerides from VLDL or chylomicrons.
• VLDL and chylomicrons then deliver the cholesteryl esters to the liver.
• HDL2 enriched with triglycerides is processed by hepatic lipase, becoming HDL3 again.
• HDL2 discharges cholesterol without endocytosis, allowing it to recycle and continue collecting cholesterol.

6. Mnemonic Rules for Apolipoproteins

• ApoA-1: Associated with HDL ("good cholesterol"); "A" for "Acquire" cholesterol and "Activate" LCAT.
• ApoB-48: Associated with chylomicrons; "forty eight" sounds like "food."
• ApoB-100: Associated with VLDL and LDL; "100 year old" man with "bad" LDL cholesterol.
• ApoC-2: "C" for "Cutting" triglycerides; activates endothelial LPL.
• ApoE: "E" for "Entregar (deliver)" to the liver; binds to LDL receptors.

7. Conclusion

Lipoprotein metabolism is a complex process involving multiple pathways, lipoproteins, and apolipoproteins. Understanding these pathways is crucial for comprehending lipid transport, cholesterol regulation, and the development of diseases like atherosclerosis. The mnemonic rules provided can aid in memorizing the functions of key apolipoproteins.