Lecture 29: Lipoproteins and Fat Metabolism

What are the fatty acid sources? (3)

• fats stored in cells as lipid droplets

• fats synthesized in one organ and exported to another

• dietary fat

True or False: 40% or more of daily energy comes from dietary fat in highly industrial societies like the U.S., but dietary guidelines suggest no more than 30% of energy from fat.

true

What are the advantages of triacylglycerol-based stores? (2 main ones)

• high energy content

  • due to fatty acids being highly reduced

• compact

  • stored in anhydrous state/lipid droplets

  • no osmotic effect on the cell

What is the disadvantage of triacylglycerol-based stores?

insoluble in water, so TAGs need special handling for transport

True or False: TAGs make up 90% of dietary fats.

true

Which enzymes digest lipids?

• lingual lipases/estrases

• gastric lipases/estrases

Describe lingual and gastric lipases.

• acid stable

• hydrolyze short and medium (12C and lower) chain fatty acids from TAGs

• most active in infants and young children who drink cows milk

• produced at the back of the tongue or in the stomach

• minimally digests most dietary fats 

True or False: Besides lingual and gastric lipase activity, much more extensive digestion of lipids occurs in the small intestine, promoted by: lipid emulsification by bile salts (detergents), pancreatic lipases, and peristalsis (mixing).

true

What is important to know about pancreatic insufficiency in cystic fibrosis?

• mutations in the CFTR (chloride channel on epithelium) cause decreased hydration and thickened secretions and the pancreatic enzymes are unable to reach the intestine

• in the affected individuals, the lingual and gastric lipases aid in degrading short- to medium-chain fatty acids despite an absence of pancreatic lipase

What shape of detergent does bile salts form?

wedge-shaped

Bile salts form what?

micelles

How do detergents solubilize/emulsify lipids?

by forming mixed micelles

How do micelles accelerate the rate of hydrolysis of lipids by lipases?

lipid emulsion greatly increases the surface-to-volume ratio of fat droplets; large fat globules are broken down into microscopic micelles

What are bile salts?

biological detergents that form emulsions/mixed micelles with lipids

Emulsification is accomplished by which two mechanisms?

• the use of detergent properties of the bile salts

• mechanical mixing due to peristalsis

Where are bile salts synthesized and what from?

synthesized in the liver from cholesterol

Where are bile salts stored?

in the gall bladder

Where are bile salts secreted?

the bile to the small intestines

What is taurine?

a form of cysteine

What is taurocholic acid (a bile acid) composed of?

• cholic acid

• taurine

Where are fats emulsified into mixed micelles by bile salts?

the small intestine

What hydrolyzes emulsified triacylglycerols and other lipids?

pancreatic lipases

What secretes pancreatic lipases?

the exocrine pancreas

When pancreatic lipases hydrolyze emulsified triacylglycerols, what is released?

fatty acids

Pancreatic lipases are also known as what?

pancreatic esterases

Pancreatic lipases preferentially remove fatty acids at which carbons?

carbons 1 and 3

Describe colipase.

• zymogen

• binds lipase at a 1:1 ratio

• anchors lipase at the lipid-aqueous interphase

Describe orlistat.

• tetrahydrolipstatin

• anti-obesity drug

• inhibits gastric and pancreatic lipases

• decreases fat absorption

True or False: Most dietary cholesterol (90%) is present in the non-esterified form.

true

What hydrolyzes cholesteryl esters?

pancreatic cholesteryl ester hydrolase/cholesterol esterase

What does the hydrolysis of cholesteryl esters by cholesterol esterase produce?

cholesterol plus free fatty acids

What greatly enhances the activity of cholesteryl ester hydrolase?

bile salts

What does phospholipase A₂ do? What does it leave?

removes 1 fatty acid from carbon 2—leaving a lysophospholipid

What does lysophospholipase do? What does it leave?

the fatty acid at carbon 1 is removed—leaving a glyceryl-phosphoryl base that is further degraded, absorbed, or excreted

Phospholipase A₂ and lysophospholipase activity is greatly enhanced by what?

bile salts

What is cholecystokinin (CCK) produced by and in the presence of what?

produced by the mucosal cells of jejunum in the presence of lipids and partially digested proteins

What does CCK do in various organs?

• the stomach to slow gastric motility

• the gallbladder to contract and release bile

• the pancreas to release pancreatic lipase

What is secretin produced in response to?

the low pH of the chyme entering the duodenum from the stomach

What does secretin cause?

causes the pancreas and liver to release bicarbonate to neutralize the pH of intestinal contents (pH ~ 5-6)

What are intestinal mucosal cells called?

enterocytes

What do micelles contain?

• 2-monoacylglycerols

• fatty acids

• free cholesterol

• fat soluble vitamins (A,D,E,K)

What is important to know about lipid malabsorption?

• increased lipid (including fat soluble vitamins and essential fatty acids) in the feces (steatorrhea)

• is caused by disturbances in lipid digestion and/or absorption

• may result from conditions such as Cystic Fibrosis (causes poor digestion) and shortened bowel (causes decreased absorption)

What is Olestra/Olean?

an artificial fat substitute

What does Olestra consist of?

a sucrose molecule with esterified fatty acids

True or False: The fatty acids in Olestra are resistant to pancreatic lipase, so it passes through the intestine intact and is eliminated in the feces. Also, Olestra can carry with it the essential fat-soluble vitamins.

true

After bile salts are emulsified and the intestinal lipases degrade TAGs, what happens?

fatty acids, cholesterol, and other lipid breakdown products are taken up by the intestinal epithelial cells

Intestinal epithelial cells re-synthesize triacylglycerols and cholesteryl esters and package them into what?

chylomicrons

What is the re-esterification process?

1. lipids absorbed by the enterocytes migrate to the ER

2. fatty acyl-CoA synthetase/thiokinase activates fatty acyls

3. MAGs are converted to TAGs by mono and diacylacylglycerol acyltransferases

4. lysophospholipids are re-acylated to form PLs by acyltransferases

5. cholesterol is re-esterified by acyl CoA:cholesterol acyltransferase

6. short- and medium-chain length fatty acids are not re-esterified

Describe lipoprotein particles.

• exterior of lipoprotein particles:

  • apolipoproteins

  • phospholipid monolayer

• interior:

  • lipid payload

• function of apolipoproteins:

  • structural

  • activate enzymes

  • receptor recognition

What are chylomicrons secreted by?

the intestinal epithelium

Describe chylomicrons.

• exterior:

  • apolipoproteins

  • phospholipid monolayer

• interior:

  • triacylglycerols

  • cholesteryl esters

  • fat-soluble vitamins

• purpose:

  • to deliver dietary fats from intestine to tissues

True or False: LPL of adipose tissue has a higher K_m than that of muscle cells, so adipose LPL is more active following a meal. Conversely, this means that muscle LPL is more active at low TAG/chylomicron and can more reliably use fatty acids for energy.

true

What is the process for how fats are digested?

1. bile salts emulsify dietary fats in the small intestine—forming mixed micelles

2. intestinal lipases degrade triacylglycerols

3. fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into triacyglycerols

4. triacylglycerols are incorporated, with cholesterol and apolipoproteins, into chylomicrons

5. chylomicrons move through the lymphatic system and bloodstream to tissues

6. lipoprotein lipase, activated by apoC-II in the capillary, converts triacylglycerols to fatty acids and glycerol

7. fatty acids are oxidized as fuel or resterified for storage

True or False: The liver has glycerol kinase while most other tissues do not. Glycerol 3-phosphate can be used for glycolysis or gluconeogenesis.

true

In the fasting state, what causes the activation of hormone-sensitive lipase?

the activation of glucagon and epinephrine

True or False: Free fatty acids and glycerol are released into the blood. Free fatty acids circulate bound to serum albumin and used by various tissues for energy.

true

How do lipoprotein particles send out lipids to the peripheral tissue and get cholesterol back from the peripheral tissues?

through lipid transport by secreting lipoprotein particles into the bloodstream

What are VLDLs and LDLs secreted by?

the liver

What are HDLs secreted by?

the liver and intestine

Describe the composition of chylomicron.

• phospholipid: 3%

• triglyceride: 90%

• cholesterol: 5%

• protein: 2%

• LARGEST

Describe the composition of VLDL.

• phospholipid: 17%

• triglyceride: 55%

• cholesterol: 20%

• protein: 8%

• SECOND LARGEST

Describe the composition of LDL.

• phospholipid: 21%

• triglyceride: 6%

• cholesterol: 53%

• protein: 20%

• SECOND SMALLEST

Describe the composition of HDL.

• phospholipid: 25%

• triglyceride: 5%

• cholesterol: 20%

• protein: 50%

• SMALLEST

Review the size of lipoprotein particles.

• HDL:

  • lowest TAG

  • high cholesterol

• LDL:

  • low TAG

  • highest cholesterol

• VLDL:

  • high TAG

  • low cholesterol

• chylomicrons:

  • highest TAG

  • lowest cholesterol

What does HDL function to?

deliver cholesterol from the peripheral tissues to the liver for elimination

What does LDL function to?

deliver cholesterol to the peripheral tissues and to the liver

What does VLDL function to?

deliver endogenous TAG to peripheral tissues

What does chylomicrons function to?

deliver dietary (exogenous) TAG to peripheral tissues

What generates HDL?

the liver and intestine

What generates LDL?

VLDL

What generates VLDL?

the liver

What generates chylomicrons?

the intestine

What is the process for chylomicron metabolism?

1. chylomicrons (CMs) are synthesized in the intestine

2. CMs pick up apoE and apoCs from the HDL

3. in adipose tissue, lipoprotein lipase (LPL) degrades triacylglycerol (TG) of CMs to fatty acids and glycerol

4. CMs remnants bind specific receptors via apo E on the surface of liver cells where the complex is endocytosed

5. CMs remnants deliver dietary cholesterol and some cellular cholesterol (via HDL) to the liver

6. CMs are cleared from circulation in over 9 hours

Metabolism of chylomicrons are what kind of pathway?

an exogenous pathway

What is the process of VLDL and LDL metabolism?

1. the liver packages TGs and cholesterol into VLDL particles for export

2. in the capillaries, LPL degrades TG to glycerol and free fatty acids, which enter the tissues by diffusion

3. further lipoprotein lipase action converts IDL into LDL particles (which contain mostly cholesteryl esters)

4. LDL receptors exist on the surface of cells in the liver and most peripheral tissues

5. the complex of LDL bound to its receptor is taken into the cell by endocytosis, thereby delivering cholesterol to the cell

What type of pathway is VLDL and LDL metabolism?

an endogenous pathway

High LDL cholesterol are correlated with what?

an increased risk of cardiovascular disease/atherosclerosis

LDL cholesterol is known as what?

bad cholesterol

What is the process for how high levels of LDL cholesterol lead to an increased risk of cardiovascular disease?

1. oxidized lipoproteins aggregate and stick to the ECM

2. monocytes attracted to the area of oxidized lipoproteins

3. monocytes differentiate into macrophage

4. foam cell (macrophage) ingests lipoproteins

5. free cholesterol accumulates in membranes as droplets

6. apoptosis, necrosis, and tissue damage

7. cholesterol-rich plaque forms

True or False: Unlike other lipoprotein particles, HDL particles are secreted “empty”. Small nascent HDL diffuse close to peripheral cell membranes, where HDL picks up the cholesterol.

true

What is the reverse cholesterol pathway?

mature HDL binds to receptors on adrenal cells, gonads, and liver—delivering cholesterol to these tissues

HDL cholesterol levels are inversely related to what?

the risk of cardiovascular disease

Describe Tangier Disease.

• a rare autosomal recessive condition characterized by low levels of HDL in the blood, accumulation of cholesterol in many organs of the body, and an increased risk of areriosclerosis

• symptoms:

  • yellow-orange colored tonsils

  • enlarged spleen and liver

  • eye abnormalities

  • neurological abnormalities

Review the recommended LDL and HDL cholesterol levels.

:)

Describe type I hyperlipidemia.

• rare autosomal recessive disorder caused by a deficiency of lipoprotein lipase or its coenzyme, apolipoprotein C-II

• results in fasting chylomicronemia and hypertriacylglycerolemia

Describe type II hyperlipidemia.

• very common

• characterized by high cholesterol levels, specifically very high blood levels of LDL

• many patients have mutations in the LDLR gene, which normally removes LDL from the circulation or apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor

Describe type III hyperlipidemia.

• removal of chylomicron remnants by the liver is decreased due to impaired binding to their receptor and accumulate in the plasma

• rare