Lipoprotein Metabolism (Exogenous and Endogenous Pathways: chylomicrons, VLDL, LDL, HDL)

1. 1

   Dietary TAG, cholesteryl esters, and phospholipids → emulsified mixed micelles

   Pancreatic lipase/colipase, phospholipase A2, cholesterol esterase (+ bile salts) 3.1.1.3 / 3.1.1.4 / 3.1.1.13 ST-0116 Irreversible/directional
   In Triacylglycerol (TAG) Cholesteryl ester Phospholipid

   Out Mixed micelle
   › Notes

   In the intestinal lumen, bile salts emulsify dietary lipids; pancreatic lipase with colipase hydrolyzes TAG predominantly to 2-monoacylglycerol plus fatty acids, phospholipase A2 hydrolyzes phospholipids, and cholesterol esterase hydrolyzes cholesteryl esters. This digestive stage is required for absorption but is not a lipoprotein-particle reaction; pancreatic lipase inhibition by orlistat reduces this flux.

2. 2

   Fatty acids/monoacylglycerol + enterocyte re-esterification → TAG; cholesterol → cholesteryl ester

   ↪ TAG; cholesterol → cholesteryl ester

   Monoacylglycerol acyltransferase + DGAT + ACAT2 (enterocyte) ST-0117 Irreversible/directional
   Out Triacylglycerol (TAG) Cholesterol
   › Notes

   Enterocytes re-form TAG mainly through the monoacylglycerol pathway (monoacylglycerol acyltransferase and DGAT) and esterify cholesterol through acyl-CoA:cholesterol acyltransferase 2 (ACAT2). These reactions use activated fatty acyl-CoA; long-chain lipids are assembled for export.

3. 3

   Nascent chylomicron assembly: TAG/cholesteryl ester + apoB-48 → chylomicron

   Microsomal triglyceride transfer protein (MTP) ST-0118 Irreversible/directional
   In TAG/cholesteryl ester ApoB-48

   Out Chylomicron
   › Notes

   Microsomal triglyceride transfer protein (MTP) loads lipids onto newly translated apoB-48 in intestinal ER; further lipidation and Golgi processing create nascent chylomicrons. ApoB-48 is generated by intestinal APOB mRNA editing and is obligatory for particle assembly; MTP-mediated apoB lipidation is the critical assembly step. Chylomicrons enter lymph, then systemic plasma via the thoracic duct.

4. 4

   Nascent chylomicron + apoC-II and apoE from HDL → mature chylomicron

   (apoC-II / apoE transfer from HDL - no enzyme) ST-0119 Irreversible/directional
   In Nascent chylomicron

   Out Mature chylomicron
   › Notes

   HDL donates apoC-II, an essential activator of lipoprotein lipase (LPL), and apoE, which mediates remnant recognition. ApoA-I and apoA-IV are also present on intestinal particles; no covalent energy-consuming reaction is required for this exchange.

5. 5

   Chylomicron TAG + H2O → fatty acids + glycerol

   Lipoprotein lipase (LPL) 3.1.1.34 ST-0120 Irreversible/directional H2O
   In Chylomicron TAG H2O

   Out Fatty acid Glycerol
   › Notes

   Endothelial LPL, activated by apoC-II and anchored by GPIHBP1, hydrolyzes core TAG. Insulin increases LPL activity in adipose tissue in the fed state, whereas cardiac/skeletal muscle LPL favors fatty-acid uptake according to local energy demand. Released fatty acids enter adipocytes for storage or muscle for oxidation; glycerol returns to liver.

6. 6

   Chylomicron → chylomicron remnant

   Lipoprotein lipase (LPL) + hepatic lipase 3.1.1.34 ST-0121 Irreversible/directional
   In Chylomicron

   Out Chylomicron remnant
   › Notes

   Continued LPL-mediated TAG removal returns apoC-II to HDL and produces a cholesterol-enriched, apoB-48/apoE-containing remnant. Hepatic lipase can further remodel remnants. This stage does not designate one single enzyme but is a sequence of intravascular lipolysis and apolipoprotein exchange.

7. 7

   Chylomicron remnant → hepatic uptake

   (receptor-mediated endocytosis via LDLR/LRP1; lysosomal acid lipase) ST-0122 Irreversible/directional
   In Chylomicron remnant
   › Notes

   ApoE binds hepatic LDL receptor (LDLR) and LDL-receptor-related protein 1 (LRP1), often aided by heparan sulfate proteoglycans; receptor-mediated endocytosis delivers remnant lipids to lysosomes. Lysosomal acid lipase hydrolyzes cholesteryl esters, and increased intracellular cholesterol suppresses HMG-CoA reductase and LDLR expression while activating ACAT-mediated re-esterification.

8. 8

   Hepatic TAG/cholesteryl ester + apoB-100 → nascent VLDL

   Microsomal triglyceride transfer protein (MTP) ST-0123 Irreversible/directional
   In ApoB-100

   Out Nascent VLDL
   › Notes

   Hepatic MTP transfers lipids to full-length apoB-100 in ER; additional TAG lipidation produces VLDL, which is secreted into plasma. Availability of hepatic fatty acids from de novo lipogenesis, adipose NEFA influx, and dietary remnants controls VLDL-TAG output. ApoB-100 is required for VLDL assembly and later serves as the LDLR ligand.

9. 9

   Nascent VLDL + apoC-II and apoE from HDL → mature VLDL

   (apolipoprotein transfer from HDL - no enzyme) ST-0124 Irreversible/directional
   In Nascent VLDL

   Out Mature VLDL
   › Notes

   HDL supplies exchangeable apolipoproteins. This prepares VLDL for capillary LPL-mediated TAG delivery, analogous to chylomicron maturation.

10. 10

    VLDL TAG + H2O → fatty acids + glycerol; VLDL → IDL

    ↪ fatty acids + glycerol; VLDL → IDL

    Lipoprotein lipase (LPL) 3.1.1.34 ST-0125 Irreversible/directional H2O
    In VLDL TAG H2O

    Out Fatty acid Glycerol VLDL
    › Notes

    LPL, activated by apoC-II, removes much of the VLDL TAG in capillary beds. ApoC-II is returned to HDL, and the particle becomes an intermediate-density lipoprotein (IDL; VLDL remnant) enriched in cholesteryl esters and retaining apoB-100 and apoE.

11. 11

    IDL → hepatic uptake or LDL

    Hepatic lipase / LDLR / LRP1 ST-0126 Irreversible/directional
    In IDL
    › Notes

    ApoE-containing IDL can be cleared by hepatic LDLR/LRP1. Alternatively, hepatic lipase hydrolyzes residual TAG and phospholipid, apoE is lost, and the particle is remodeled to cholesteryl-ester-rich LDL, which contains apoB-100 as its sole major apolipoprotein.

12. 12

    LDL + LDLR → endocytosed LDL; cholesteryl ester → free cholesterol

    ↪ endocytosed LDL; cholesteryl ester → free cholesterol

    (LDLR-mediated endocytosis; lysosomal acid lipase; PCSK9 regulation) ST-0127 Irreversible/directional
    In LDL LDLR

    Out Endocytosed LDL Cholesteryl ester
    › Notes

    ApoB-100 binds LDLR, triggering clathrin-mediated endocytosis. Endosomal acidification releases LDL from receptor; LDLR normally recycles, while lysosomal acid lipase releases free cholesterol. PCSK9 directs LDLR toward lysosomal degradation rather than recycling and thereby raises circulating LDL.

13. 13

    Cellular cholesterol feedback: free cholesterol → storage and reduced synthesis/uptake

    ACAT1 / ACAT2 2.3.1.26 ST-0128 Irreversible/directional
    In Free cholesterol
    › Notes

    ACAT1/ACAT2 esterify excess intracellular cholesterol for storage. Cholesterol suppresses SREBP-2 activation, reduces HMG-CoA reductase and LDLR transcription, and promotes HMG-CoA reductase degradation. Macrophage uptake of modified LDL through scavenger receptors (e.g., SR-A and CD36) is not feedback down-regulated and promotes foam-cell formation.

14. 14

    ApoA-I + phospholipid → nascent discoidal HDL

    ABCA1 (cholesterol/phospholipid efflux transporter) ST-0129 Irreversible/directional
    In ApoA-I Phospholipid

    Out Nascent discoidal HDL
    › Notes

    Liver and intestine secrete lipid-poor apoA-I. Peripheral-cell cholesterol and phospholipid are exported to apoA-I via ABCA1, forming nascent discoidal HDL; ABCA1 activity is induced by liver X receptor (LXR) in response to cellular oxysterols.

15. 15

    Free cholesterol in HDL + phosphatidylcholine → cholesteryl ester + lysophosphatidylcholine

    Lecithin:cholesterol acyltransferase (LCAT) 2.3.1.43 ST-0130 Irreversible/directional
    In Phosphatidylcholine

    Out Cholesteryl ester Lysophosphatidylcholine
    › Notes

    Lecithin:cholesterol acyltransferase (LCAT), activated by apoA-I, esterifies HDL-surface cholesterol. The cholesteryl ester moves into the hydrophobic core, converting discoidal HDL into mature spherical HDL and maintaining a gradient for additional cholesterol efflux.

Overview

Because triacylglycerols and cholesteryl esters are hydrophobic, human plasma transports them in lipoproteins: particles with a hydrophobic core and an amphipathic surface of phospholipid, free cholesterol, and apolipoproteins. The exogenous pathway carries dietary lipid in chylomicrons; the endogenous pathway exports hepatic TAG in VLDL and delivers cholesterol through LDL. HDL participates in reverse cholesterol transport and exchanges apolipoproteins and lipids with other particles.

Cellular location

Chylomicron assembly occurs in enterocyte ER and Golgi; VLDL assembly occurs in hepatocyte ER and Golgi. Intravascular TAG hydrolysis takes place on the luminal endothelial surface of adipose, cardiac, and skeletal-muscle capillaries, where lipoprotein lipase is tethered by GPIHBP1. LDL uptake occurs broadly through LDL receptors, especially in liver; reverse cholesterol transport involves peripheral cells, macrophages, plasma HDL, and liver.

Net energetics

There is no single universal ATP yield for lipoprotein metabolism because it is a transport, remodeling, and receptor-trafficking system rather than a single catabolic pathway. Energetic costs include fatty-acid activation (2 ATP equivalents per acyl-CoA), TAG/cholesteryl-ester synthesis, apoB translation, MTP-dependent ER assembly, and receptor-mediated endocytosis; LPL and hepatic-lipase hydrolysis consume water but do not directly produce ATP. The energy carried by lipoprotein TAG is released only after tissue uptake and β-oxidation of its fatty acids, whereas HDL-mediated cholesterol return supports biliary elimination rather than ATP production.

Clinical significance

Lipoprotein metabolism coordinates dietary-fat delivery, hepatic export of surplus TAG, cholesterol delivery, and reverse cholesterol transport. Deficiency of LPL or apoC-II causes severe fasting chylomicronemia and pancreatitis risk; MTP deficiency causes abetalipoproteinemia with fat malabsorption, acanthocytosis, and neurologic complications from fat-soluble-vitamin deficiency. LDLR, apoB, or PCSK9 gain-of-function variants cause familial hypercholesterolemia, characterized by markedly elevated LDL and premature atherosclerotic cardiovascular disease. Atherosclerosis results in part from retention and modification of apoB-containing particles in the arterial wall and unregulated macrophage scavenger-receptor uptake, whereas HDL function—not merely HDL-cholesterol concentration—relates to reverse cholesterol transport. Amino acid and nitrogen metabolism describes how the body processes dietary and endogenous protein, interconverting amino acid carbon skeletons with central energy metabolism while safely disposing of nitrogen as urea. This category also covers the one-carbon and methylation networks and heme biosynthesis/degradation that depend directly on amino acid chemistry. Defects in these pathways produce some of the best-characterized inborn errors of metabolism, making this category central to clinical genetics and nutrition.