Lipoprotein Transport and Metabolism

Lipids are packaged into chylomicrons and transported.
Lipid hydrolysis by lipoprotein lipase results in fatty acids absorbed by cells or transported in blood bound to albumin, and glycerol is released.
Transport and metabolism of very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
Difference between exogenous and endogenous pathways of lipoprotein metabolism.
HDL reverse cholesterol transport pathway.

Dietary intake.
Endogenous cholesterol synthesis, mainly in the liver.
During circulation, adipose tissue and muscles extract triacylglycerols (TAG) from VLDL, resulting in LDL formation.
Obstructive liver disease impairs bile acid secretion into the intestine.

HMG CoA reductase is involved in more than just cholesterol synthesis.
It converts HMG CoA to mevalonate.
It is also involved in:
- Isopentenyl adenine (transfer RNA).
- Prenylation of signaling peptides (ras, rho, etc.).
- Ubiquinones (CoQ-10, etc.).
- Dolichols.
Inhibition of other key products of mevalonate may relate to nonlipid effects and rare side effects of statins.
Inhibited by statins.
Integral membrane protein of the endoplasmic reticulum (ER).
Increased precursor of cholesterol.
Rate-limiting and key regulated step in cholesterol synthesis.

Divided into:
- Exogenous pathway: Starts with the synthesis of chylomicrons by the intestine, formed after a meal from dietary TAG.
- Endogenous pathway: Starts with the synthesis of very low-density lipoprotein (VLDL) by the liver.

Cholesterol Intake: $400$ mg/day
Cholesterol Synthesis: $1,300$ mg/day
Cholesterol Storage: $17,400$ mg/day
Cholesterol Excretion: $850$ mg/day
Steps:
1. Cholesterol enters the duodenum, and bile salts are released into the intestine, acting as emulsifiers to break down large fat droplets into smaller micelles.
2. Uptake by intestinal cells: Micelles containing cholesterol and other lipids contact the brush border membrane of enterocytes. Cholesterol is taken up by enterocytes through active transport processes mediated by specific transporter proteins such as NPC1L1.
3. Incorporation into chylomicrons: Inside the enterocytes, absorbed cholesterol is packaged along with other lipids (triglycerides and phospholipids) into chylomicrons. Chylomicrons transport dietary lipids from the intestine to the bloodstream via the lymphatic system.
4. Transport to the liver: Chylomicrons travel through the lymphatic system and enter the bloodstream, delivering dietary lipids, including cholesterol, to various tissues. Some chylomicrons are taken up by the liver for further processing and utilization.
Occurs in the small intestine (duodenum and jejunum).

Inhibition of NPC1L1 by Ezetimibe for Hypercholesterolemia and Sitosterolemia.
Sitosterolemia: Rare genetic disorder characterized by the accumulation of plant sterols, including sitosterol, in the blood and tissues.
- Drugs, e.g., Ezetimibe, target cholesterol transporters, not good back to 20%.
Nascent chylomicron formation:
- Low free cholesterol → cholesterol ester.
- Involves Apo proteins and lipids.

Microsomal triglyceride transfer protein (MTP) is essential for the assembly of apo B48-containing particles in ER.
The particles are packaged in secretory vesicles in the Golgi after which they fuse with the plasma membrane releasing the LP.
Newly synthesized TAG and CE are hydrophobic and aggregate; therefore, they must be packaged as stabilized particles (structure of LP).
Defect in MTP leads to inability to load apo B with lipid and abetalipoproteinemia.
Few VLDL or CM are formed, and TAG accumulates in the liver and intestine.
Absorption of fat-soluble vitamins is decreased.
LDL levels are low.

Apo C rich.
Mature chylomicrons found in adipose tissue and blood vessels.
Lipoprotein lipase is activated by apoC.
Free fatty acids are released as triacylglycerols in chylomicrons degrade to glycerol.

Synthesized by adipose tissue, cardiac, and skeletal muscle. Highest concentration is in cardiac muscle.
Regulated by nutritional state and hormones.
- Fed state (elevated insulin) increases LPL synthesis in adipose tissue but decreases it in muscle.
- Fasting (decreased insulin) favors LPL synthesis in muscle.
Diabetes mellitus impacts LPL.

Conversion to low-density lipoproteins: VLDL is converted in the plasma to LDL. Intermediate-sized particles, the intermediate-density lipoproteins (IDLs), or VLDL remnants, are observed during this transition. IDLs can also be taken up by liver cells through receptor-mediated endocytosis that uses apo E as the ligand.
Hepatic lipase, LDL receptors, and peripheral tissue are involved.

PCSK9 is a natural circulating inhibitor of the LDLR. PCSK9 targets the receptor for degradation following endocytosis.
PCSK9 and LDLR genes are co-regulated by intracellular cholesterol content and statin treatment (mainly expressed in the liver).
PCSK9 levels are increased in T2D.
Targeting plasma PCSK9 is conceptually a promising approach to lower LDL-C levels in monotherapy as well as on top of statins.
- Responsible for removing LDL (cholesterol rich) from the bloodstream.

Selective transfer of cholesterol from peripheral cells to HDL, from HDL to the liver for bile acid synthesis or disposal via the bile, and to steroidogenic cells for hormone synthesis.
Basis for the inverse relationship seen between plasma HDL concentration and atherosclerosis and for HDL's designation as the "good" cholesterol carrier.
Exercise and estrogen raise HDL levels.
Involves efflux of cholesterol from peripheral cells to HDL, esterification of the cholesterol by LCAT, binding of the cholesteryl ester-rich HDL (HDL2) to liver (and steroidogenic cells), the selective transfer of the cholesteryl esters into these cells, and the release of Lipid depleted HDL (HDL3).