Storage and Transport of Lipids in the Postprandial State

Transport of lipids in the circulation:

Chylomicron is a lipoprotein:

• Lipids are hydrophobic (or “water hating”), but they need to be delivered to tissues for many purposes

• Phospholipids, triglycerides, cholesterol, and cholesteryl esters (cholesterol plus fatty acid) can be packaged with proteins into a hydrophilic (or “water loving”) macromolecule complex called a lipoprotein

Lipoprotein Particles

• Carry cholesterol and other lipids

• Lipids are carried through the plasma on spherical particles.

  • Surface is made of protein (called apolipoprotein) and a phospholipid monolayer

  • interior contains cholesterol, triglycerides, and cholesteryl esters

Four Major Classes of Lipoprotein Particles

• Named based on position of sedimentation (density) in centrifuge (density is directly proportional with percent protein content and percent phospholipid content; inversely proportional to triglyceride content)

• Composition varies between class of lipoprotein

• Includes four major classes:

  • Chylomicrons

  • VLDL

  • LDL (bad cholesterol)

  • HDL (good cholesterol)

Lipoprotein Metabolism

Main function: transport lipids in the blood

• Exogenous lipid transport system

• Endogenous lipid transport system

Exogenous lipid transport system:

• Transports triacylglycerols from the intestine to peripheral tissues for storage or energy utilization

• Chylomicrons disappear after all dietary triacylglycerols are delivered

Packaging of chylomicron:

1. Fatty acids enter the enterocyte:

• Dietary triglycerides are digested in the intestinal lumen into FA and other products

• FA are taken up by the enterocyte (intestinal epethelial cell)

2. Cholesterol enters the enterocyte → primarily by NPC1L1

3. FA are reassembled into triglycerides inside the enterocyte

• These triglycerides will become the major component of the chylomicron

4. Some cholesterol is converted into cholesterol ester inside the enterocyte via ACAT

• Makes cholesterol more suitable for packaging into a lipoprotein

5. ABCG5/ABCG8 transports cholesterol back out of the enterocyte and into the intestinal lumen

• Mechanism that limits how much cholesterol is absorbed

6. The enterocyte combines TG, CE, and ApoB-48 to form a chylomicron with the help of MTP

7. Chylomicron enters the lymph

Chylomicrons (CM)

• Deliver triglycerides from the intestines that are derived from food intake.

• Each particle contains one ApoB-48 molecule

• Microsomal triglyceride transfer protein (MTTP or MTP) mediates the lipidation of apoB48 in enterocytes.

• The size varies depending on the amount of fat ingested.

  • A high fat meal leads to large CM particles, while in the fasting state the CM particles are small carrying lower quantities of triglyceride.

• The amount of cholesterol carried by CM can also vary depending upon dietary intake.

Exogenous lipoprotein pathway:

1. Intestine → lymph

• TG and cholesterol are packaged into chylomicrons

2. Lymph → blood

• Chylomicrons enter the bloodstream

3. LPL (activated by Apo-CII) removes TG and releases FA for muscle, heart, and adipose tissue

4. Chylomicron remnant (particle after losing most TG)

• Rich in cholesterol

5. Remnant → liver (via LDL receptor (LDL-R))

ApoB-48

Structure of chylomicron

ApoC-II

Activates LPL

ApoE

Helps remnant enter the liver

LPL

• Breaks down (hydrolyzes) TG → FA

• Synthesized by the cells in tissues such as muscle (skeletal and myocardium), adipocytes and the mammary gland

• Needs heparan sulfate proteoglycans (HSPG) on the surface of the cells

• Acts on CM to hydrolyze TG into glycerol and free fatty acids (FFA)

• Regulated by several factors - insulin, ApoC-II and ApoC-III

HDL

Gives ApoC-II and ApoE to chylomicrons

Hepatic Lipase

Helps liver process remnants

LRP

Liver receptor for chylomicron remnants

FFA

• Stored in adipocytes

• Glycerol (from TG breakdown) is taken up by the liver to fuel gluconeogenesis in fasting, and TG synthesis to make VLDL in the fed state.

• Some remain in the circulation - referred to as spill over FAs, which are taken up by the liver and repackaged as TG and secreted as VLDL.

Insulin

Reduces flux of free fatty acids to the intestine, and inhibits MTP

What does insulin do to chylomicron secretion?

Decrease chylomicron secretion

What does insulin resistance do?

Increase chylomicron production

What enzyme acts on chylomicrons in the blood?

LPL

What does ApoC-II do?

Activates LPL

What does ApoC-III do?

Inhibits LPL activity:

• the gene makes a protein of about 8 kilodaltons; this protein gets glycosylated in the Golgi

What does ApoE do?

Helps the liver take up chylomicron remnants

What happens to chylomicrons after LPL acts on them?

They lose TG → become cholesterol-rich remnants

What enzyme helps process chylomicrons/remnants?

LPL, hepatic lipase, and endothelial lipase

Where do chylomicron remnants go?

The liver

What receptors help the liver take up remnants?

LDL receptor, LRP-1, SR-B1, and Syndecan-1

What stimulates chylomicron remnant uptake?

ApoA-V

What inhibits chylomicron remnant uptake?

ApoC-III

What happens if chylomicron metabolism is delayed?

Remnants accumulate → more atherogenic

What are the main inhibitors of ApoC-III?

Insulin and polyunsaturated fatty acids

What are the main enhancers of ApoC-III?

Glucose, fructose, and saturated fatty acids:

• Diets very rich in sugar or saturated fat