Lipid Digestion

Front 1

5 functions of lipids

Back 1

1. Energy source

2. Membrane components

3. Storage

4. Regulatory functions (white adipose - steroids, eicosanoids, cytokines, hormones)

5. Thermogenesis (brown adipose - mediated by thermogenin/UCP)

Front 2

What happens to polyunsaturated fats when they are fed to ruminants?

Back 2

The majority are converted to saturated fats.

Front 3

What happens to lipids in the rumen?

Back 3

- Broken down via hydrolysis into their components (fatty acids/sugar plus a glycerol)

- The FAs are biohydrogenated by microbes

- Glycerol fermented by microbes to make VFAs, eventually encorporated (along with fatty acids) as phospolipids

- Some fat or FAs bypasses rumen

Front 4

How does biohydrogenation work in the rumen?

Back 4

- Linoleic acid (18:2) is converted to rumenic acid (CLA) by isomerase and then to vaccenic acid (trans 18:1) and finally stearic acid (18:0)

- During altered fermentation (ie high grain), linoleic acid may get converted to a different CLA by isomerase

Front 5

What are the rate limiting steps of biohydrogenation?

Back 5

- From the trans 18:1 to stearic acid (IE vaccenic acid, or the equivalent in the altered fermentation pathway)

Front 6

What kind of fat sources are protected in the rumen?

Back 6

Calcium salt fatty acids

Front 7

What microbes help with fat hydrolysis in the rumen?

Back 7

- A. lypolytica bacteria

- Protozoal lipase, galactosidase, phospholipase

- Microbes also ferment glycerol

Front 8

What happens to long chain fatty acids in the rumen?

Back 8

- Not a major source of energy for microbes (toxic)

- Some microbial synthesis (incorporation in structure/cytosol)

- But mostly SFAs, a few MUFAs, no PUFAs

Front 9

Is duodenal flow of FAs greater or less than FA intake?

Back 9

It is greater, because the microbes can synthesize more FAs.

- Microbes can synthesize new SFAs from acetate and glucose

- Or straight chain odd carbon FAs from propionate and valate

Front 10

General overview of lipid digestion and absorption

Back 10

- Lypolysis by enzymes

- Bile acids emulsify FAs and MGs - micelle formationa

- Absorbed into the cell, where everything is re-esterified to form TGs in chylomicrons

- MTP (microsomal TG transfer protein) helps assemble apo-B48 which is needed on chylomicrons

- Chylomicrons enter lymph via exocytosis, which eventually get to circulation via thoracic duct (bypassing liver for now)

- SCFAs and MCFAs can just go to portal circulation directly (less than 12C)

Front 11

What are chylomicrons made of?

Back 11

Core: nonpolar lipids (TGs), cholesterol ester

Surface: proteins and polar lipids (phospholipids), free cholesterol

Front 12

4 causes of steatorrhea

Back 12

Steathorrhea: excess fat in feces

1. Bile salt deficiency (due to liver disease, bile duct obstruction, disrupted enterohepatic bile salt recycling, bacterial overgrowth which converts bile salts to bile acids)

2. Pancreatic enzyme deficiency (due to pancreatitis, duct obstruction, gastric hyperacidity)

3. Defective chylomicron synthesis

4. Lymphatic obstruction

Front 13

What happens to the chylomicron after it leaves the intestine?

Back 13

- Intestine makes chylomicrons and HDL. Both end up in circulation.

- HDL donates Apo protein C to the chylomicron, making it mature, and helping it go to the tissues

- The enzyme lipoprotein lipase along with an Apo C receptor can "grab" CMs. This is found on capillaries at peripheral tissues, so these tissues can use (hydrolyze) the TGs.

- The chylomicron remnant is endocytosed by the liver, mediated by an Ape E receptor.

Front 14

What happens to chylomicron remnants after they return to the liver?

Back 14

- The liver repackages TGs and cholesterol that were in the CM remnant into very low density lipoprotein (which has ApoB100)

- VLDL can be hydrolyzed by peripheral tissues via the Apo C receptor and LPL enzyme (same as CM mechanism).

- Now the VLDL is an LDL or IDL

- IDLs and VDLs are endocytosed by the liver or peripheral tissues, mediated by Apo B100 receptors

- HDL also transports cholesterol from tissues back to the liver (SRB1 receptor)

Front 15

Why are cattle especially prone to fatty liver?

Back 15

Because they have a limited capacity to export VLDL, therefore creating a bottleneck in the liver.

Front 16

General lipid metabolism chart

Back 16

Front 17

How are triglycerides synthesized?

Back 17

Where: liver and adipocytes (cytoplasm and smooth ER)

Substrate: FAs (from denovo synthesis, diet, or TAGs) or glycerol-3-P (from glycolysis for TAGs) or dihydroxy acetone phosphate

Enzyme: Glycerol-3-P Acyl Transferase

Front 18

What enzymes are involved in triglyceride break down?

Back 18

- Desnutrin (activated by glucocorticoids, inhibited by insulin)

- Hormone Sensitive Lipase (activated by epinephrine and glucagon, inhibited by glucagon)

- Monoglyceride Lipase

Front 19

What happens to fatty acids in the cell?

Back 19

- Fatty acids enter the cell.

- Fatty acids are transported by FABP (fatty acid binding protein) to their destination: either FA synthesis or beta oxidation

- CPT1 controls entry to mitochondria. Once in mitochondria = beta oxidation and TCA cycle

Front 20

Describe de novo synthesis of fatty acids in the cytoplasm.

Back 20

Substrates:

- Ruminants: acetate and butyrate in adipose, glucose in muscle adipocytes

- Nonruminants: Glucose

- Enzyme ACC turns Acetyl-CoA to Malonyl Co-A

- Enzyme FAS uses Malonyl-CoA to make the fatty acid

- More enzymes elongate the fatty acid: 2 carbons added per cycle

- Enzyme desaturase can add a double bond (but not beyond C9)

Front 21

What are the rate limiting enzymes in de novo fatty acid synthesis? What inhibits or stimulates them?

Back 21

- Acetyl CoA carboxylase (ACC)

- Fatty acid synthase (FAS)

Activators: insulin, citrate

Inhibitors: NE, glucagon, fatty acyl CoA

Front 22

What are the primary sites of fatty acid synthesis in the different species?

Back 22

Ruminants: adipose, mammary

Humans and birds: liver

Rodents and rabbits: liver, adipose

Dogs, cats, pigs: adipose

Secondary sites:

Humans: adipose

Dogs and cats: liver

Front 23

What happens in the mitochondria during beta oxidation?

Back 23

- Fatty acyl CoA (from the diet or de novo synthesis) enters the mitochondria via CPT

- Beta oxidation to acetyl CoA

- This repeats for every "link the the chain"

- ATP is made! 129 ATP/palmitate molecule (TCA cycle and ETS)

Front 24

What is the control point for entry to the mitochondria?

Back 24

Carnitine palmitoyl transferase (CPT) and the carnitine shuttle system, which uses CPT1,CPT2 and CAT.

CPT1 is inhibited by malonyl co-A (reciprocal control mechanism) and insulin. It is stimulated by glucagon.

Front 25

Names of the 3 lipogenesis (TAG synthesis) pathways

Back 25

1. Glycerol to phosphatidate in the liver

2. DHAP in the liver

3. MAG in the intestinal mucosa

Front 26

How does fatty acid metabolism happen in the liver?

Back 26

- Fatty acid synthesis: Acetate becomes acyl-coA

- Acyl-CoA goes into mitochondria via CPT1 if energy is needed. (If not, they are turned into TGs and sent out as VLDL)

- The Acyl-CoA goes through the TCA cycle, which requires oxaloacetate

- The oxaloacetate comes from proproniate (Therefore, if there is not enough proprionate, the Acyl-CoA can't go through the TCA cycle)

- Oxaloacetate can also be used to make glucose.

Front 27

Why does ketosis happen?

Back 27

- If there is not enough oxaloacetate available to keep up with the amount of Acyl-CoA, the Acyl-CoA can't go through the TCA cycle. Instead, it becomes acetoacetate.

- Acetoacetate becomes BHBA and acetone. These 3 are ketones.

- This may occur in situations where FA mobilization (alot of of NEFAs in blood) overwhelms the liver (IE negative energy balance). Common example is lactating dairy cows.

Front 28

Where can ketones be used for energy?

Back 28

Ketones can be used as energy in the heart, muscle and brain (but not the liver, because it lacks CoA transferase).

Front 29

In cattle, what is the limiting factor of VLDL production?

Back 29

Cattle have a limited capacity to make ApoB100. This makes them especially prone to fatty liver.

Front 30

Ketone Body Oxidation diagram.

What enzyme is important?

Back 30

Important enzyme: Beta-ketoacyl CoA Transferase

- Allows ketone to enter TCA cycle

- Not in liver

Front 31

What is the rate limiting enzyme in cholesterol synthesis?

Back 31

HMG CoA reductase

(This is what cholesterol drugs target.)

Front 32

Where is cholesterol synthesized?

Back 32

- Primarily in the liver (50%) and intestine (15%)

- Also in the skin, adrenal cortex, ovaries, testes and placenta

Front 33

3 Outputs of Cholesterol Metabolism (and enzymes)

Back 33

- Re-esterification (enzyme ACAT)

- Biosynthesis of bile salts/steroids

- Transfer to HDL (enzyme LCAT)