Major Classes of Lipoproteins
Lipoprotein particles vary in density, size, and composition:
- VLDL (Very-Low-Density Lipoproteins): Transport endogenous fats from the liver primarily to adipose tissue. They have a diameter of 30–100 nm and a density of 0.96–1.00 g/mL. The main lipid component is triacylglycerols (TAG), making up about 55% of the mass. The principal apolipoprotein is apoB-100.
- LDL (Low-Density Lipoproteins): Formed in the circulation during lipolysis. Approximately 50% of their composition consists of cholesterol and cholesterol esters.
- HDL (High-Density Lipoproteins): Responsible for the "reverse cholesterol transport" by scavenging excess cholesterol from cell membranes and other blood lipoproteins, as well as serving as apolipoprotein donors.
- Chylomicrons (CM): Formed in the intestine, transporting exogenous (dietary) fats. Their marker apolipoprotein is apoB-48.
Formation and Maturation of VLDL
VLDL synthesis occurs in hepatocytes. The liver maintains a total cholesterol pool comprising both exogenous (dietary) and endogenous (de novo synthesized) cholesterol.
Along with TAGs, this cholesterol is packaged into immature VLDL. A critical role in this process is played by the microsomal triglyceride transfer protein (MTP), which transfers TAGs into the nascent lipoprotein particle. The structural backbone is provided by the apoB-100 protein.
Upon entering the bloodstream, immature VLDL particles encounter HDL, from which they acquire apoE and apoC-II. Only after acquiring these apolipoproteins do VLDL particles become mature and fully functional.
HDL Metabolism and Cholesterol Ester Transport
HDL is synthesized in the liver and intestine as immature (discoid) particles. Immediately upon entering the circulation, they act as donors of apoC-II and apoE to chylomicrons and VLDL.
Nexting begins the scavenging function: HDL picks up excess cholesterol. The enzyme lecithin-cholesterol acyltransferase (LCAT), activated by apoA-I, operates on their surface. LCAT converts free cholesterol into cholesteryl esters (CE) and sequesters them into the hydrophobic core of the particle.
As cholesteryl esters accumulate, the discoid particle transforms into spherical HDL₃, and upon further enrichment, into larger HDL₂. Subsequently, cholesteryl ester transfer protein (CETP) acts to transfer CEs from HDL to LDL or VLDL in exchange for TAGs.
To complete the cycle, hepatic lipase on the surface of hepatocytes hydrolyzes TAGs within HDL₂, reducing their size and converting them back into HDL₃.
Mechanisms of Cholesterol Return to the Liver
The collected cholesteryl esters return to hepatocytes via three pathways:
- Endocytosis via LDL Receptors (Primary pathway): Hepatic receptors recognize apoB-100 and apoE located on the surface of remnant chylomicrons, IDL, and LDL.
- Scavenger Receptors (SR-B1): This pathway mediates the selective uptake of cholesteryl esters from HDL into hepatocytes, especially following modification by hepatic lipase.
- HDL Endocytosis (Minor pathway): A small fraction of HDL is endocytosed intact by cells via interactions between its apolipoproteins and specific receptors.
Isoforms of Lipoprotein Lipase (LPL)
Lipoprotein lipase, the enzyme responsible for hydrolyzing triglycerides within lipoproteins, exists in tissue-specific isoforms that differ in substrate affinity as represented by the Michaelis constant ($K_m$):
- In adipose tissue, the $K_m$ is high (low affinity). The enzyme is active only in the postprandial (absorptive) state when circulating lipoprotein concentrations are high. Its primary role is energy storage during nutrient abundance.
- In skeletal muscle, the $K_m$ is low (high affinity). Muscle tissue can efficiently utilize fatty acids even at low circulating concentrations, which is essential for a continuous energy supply during muscular work.