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

1. 16

   HDL cholesteryl ester → liver directly or to apoB particles indirectly

   SR-BI (selective uptake) / CETP (cholesteryl ester transfer protein) ST-0131 Irreversible/directional
   In Cholesteryl ester

   Out Cholesterol
   › Notes

   HDL delivers cholesteryl esters directly to liver/steroidogenic tissues through scavenger receptor class B type I (SR-BI) selective uptake. Alternatively, cholesteryl ester transfer protein (CETP) exchanges HDL cholesteryl ester for TAG from VLDL/IDL/LDL; the apoB-containing particles can then be cleared by liver. Hepatic lipase and endothelial lipase remodel HDL and influence HDL particle size and turnover.

2. 17

   Hepatic cholesterol → bile acids/free cholesterol → biliary secretion or enterohepatic recycling

   ↪ bile acids/free cholesterol → biliary secretion or enterohepatic recycling

   Cholesterol 7-alpha-hydroxylase (CYP7A1) 1.14.14.23 ST-0132 Irreversible/directional
   In Cholesterol

   Out Bile acid
   › Notes

   Liver disposes of cholesterol by secretion into bile and by conversion to bile acids, initiated by cholesterol 7α-hydroxylase (CYP7A1). This terminal stage completes reverse cholesterol transport and is a major route of cholesterol elimination from the body.

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.