Fat Metabolism

This lecture will review all the ways in which fats/fatty acids are taken in, stored, and metabolized within the human body.

We will start off with a review of the different structures that various fats come in, from fatty acids, cholesterol, phospholipids, etc. We will review what makes a fat “saturated versus “unsaturated.”

We follow that with an overview of the digestion and absorption of fats. We will explore the organs and enzymes involved in that process, notably the liver and gall bladder for bile production. We talk about what happens to fats once they enter the body, how they are transported to adipose tissue or metabolized.

We will talk about specific processes related to the anabolism and catabolism of fats, including:

The conversion of carbs into fats
The mobilization of fatty acids from adipose tissue
How fatty acids are converted into acetyl-CoA and eventually ATP
The production and use of ketone bodies
Cholesterol metabolism
Phospholipid biology
Omega 3/6 signaling

Key Takeaways

Identify various types of fats/lipids
Understand how fats are digested and absorbed
Know what happens to dietary fat in an energy rich state and energy poor state
Understand, at a high level, how fatty acids are broken down through beta-oxidation
Know where ketones are created, and from what point that creation begins
Understand how cholesterol, phospholipids and omega-3 and 6 eicosanoids impact metabolism and overall cellular biology

[Metabolism Key Terms]

Lipid Structure

Lipids come in more diversity.

Saturated fatty acids are acids that only have single bonds unsaturated fatty acids have a double bond in the structure somewhere. This creates a kink which makes this lipid less densely packed than saturated

Triglyceride is a backbone that can link un/saturated fatty acids

Steroids and Cholesterol is still considered lipids

Lipid Digestion and Absorption

[liver] and [gallbladder]

The liver is responsible for a large number of functions, but specific to digestion its responsible for the production of bile
[Bile] is then sent to the gallbladder for storage — which extracts water out of Bile to make it more concentrated
[Bile] is partially responsible for the digestion of fats to fatty acids

Fat Digestion

The majority of dietary fat comes in the form of triacylglycerol, along with some cholesterol and small amounts of phospholipids
Fat soluble vitamins are also absorbed as well (such as vitamin A)
Digestion of fat necessitates that the lipid molecules are accessible by enzymes, which requires a step called emulsification

Bile salts take a big fat globule and break them down into much smaller pieces… Emulsification

A small amount of fat digestion of fat occurs in the stomach, by gastric lipase
However, most of the digestive process occurs in the small intestine, due to the production of pancreatic lipase
For [lipase] to access fat, emulsification must occur
- Bile salts, produced by the liver and concentrated by the gall bladder are released into the small intestine
- Bile salts stabilize the hydrophobic aspects of the lipids, allowing for smaller and smaller “droplets” to be formed
- As they become smaller, pancreatic lipase is able to access the triacylglycerols and begin hydrolysis to form free fatty acids

the lipids get packaged up as Chylomicrons in the epithelial cell layer. They enter the Lacteal which get transported into the lymph system

Fat Absorption and Transport

Transporters bring micelles through the membrane into the GI epithelial cells
Once inside, fatty acids reform triacylglycerol, are packaged with cholesterol, phospholipids and ApoB, and shipped out into the lacteal as “Chylomicrons”
Chylomicrons pass into the lymphatic system, eventually reaching the circulatory system, where they are slowly broken down by adipose tissue, leaving only a cholesterol dense particle that is removed by the liver

Fatty Acid Uptake by Adipocytes

Adipose tissue produces an enzyme called lipoprotein lipase (LPL), which is secreted and then bound to the surface of blood vessels
LPL slowly breaks down the chylomicrons into smaller sizes, liberating fatty acids for uptake into the adipocytes
Fatty acids reform triacylglycerides in the adipocytes

The body transforms single fatty acids to triacylglycerides and back when it needs to go in and out of cells

Lipogenesis

So you ate a tooonnn of carbs..

The process of creating long chain fatty acids for long term storage of energy
Stimulated by high levels of citrate
End process of lipogenesis is a triacylglycerol called “Palmitate” or sometimes “Palmitic Acid”
Requires a good amount of ATP and NADH
Biotin dependent process

High concentrations of Acetyl-CoA. First signal that storing food.

The process of lipogenesis begins with acetyl-CoA… but it has to occur in the cytosol of the cell
Acetyl-CoA cannot move outside of the mitochondria so the acetyl-CoA “hides” within citrate which CAN leave the mitochondria
Citrate is broken down into Oxaloacetate and acetyl-CoA
Acetyl-CoA (2C) converts to Malonyl- CoA (3C)
Oxaloacetate forms pyruvate
- Which in turn cycles back into the mitochondria to get stored as acetyl-CoA
Lipogenesis begins with malonyl-CoA being reduced to [butyrate], a SHORT chain fatty acid
This process repeats itself 6 more times to make a long chain fatty acid called palmitate
- Will repeat this three times until all three docking stations
Palmitate can be modified or desaturated to form other fatty acids
The liver is the primary location for lipogenesis, however adipose tissue can run this process as well
The triglycerides are sent out from the liver and taken up by adipose tissue and skeletal muscle

Summary of Lipid Biology in an Energy Rich State

Fatty acids are absorbed from the GI tract and packaged as chylomicrons
Chylomicrons travel to the adipose tissue, where it is broken down by LPL and taken into the adipocyte -> Long-term storage of fats as TAG
Excess glucose can be converted into fatty acids through lipogenesis
Triglycerides are transported as lipoproteins to the adipose tissue -> Long-term storage of fats as TAG

Lipolysis

The breakdown of triglycerides stored in adipocytes
Stimulated by the presence of glucagon (“Glucose-Gone”) and/or epinephrine
Enzymes turn a TAG into a DAG, which gets turned into a MAG, which is finally turned into glycerol
- Adipose triglyceride lipase
- Hormone sensitive lipase
- Monoacylglycerol lipase
Insulin inhibits this full pathway
- What does this mean for insulin resistance???

The body doesn’t waste anything

Fatty acids can be pulled into muscle and used if theres a lot of fatty acids and low glucose the muscle will use the fatty acids.

How are Fatty Acids processed into energy

First an acyl-CoA group is added to “activate” the fatty acid
Requires ATP

Fatty acids can’t get through mitochondria membrane

Next, a complex series of reactions occurs to essentially move the fatty acyl-CoA inside the mitochondria
Called the “Carnitine Shuttle”
Finally, a process called Beta Oxidation occurs, removing 2 carbons from the end of the fatty acid at a time
Produces Acetyl-CoA, which enters into the TCA, leading to ATP generation

to use fatty acids as fuel, you need carnitine!

Signs of carnitine deficiency

Decreased or floppy muscle tone or muscle weakness
Tiredness (fatigue)
Irritability
Delayed movement (motor) development
Poor feeding in a baby
Symptoms of low blood sugar (hypoglycemia) if the liver is affected
Swelling (edema) or shortness of breath, if the heart is affected

Waking up hungry in the night.

Beta-Oxidation

Try to pull two carbons off a fatty acid. Cleave the beta-carbon will happen 7 times

Long chain fatty acids are “attacked” at the 2nd C position
End product is acetyl-CoA, NADH, FADH2
A 16 carbon fatty acid can make 8 acetyl-CoA, 7 NADH and 7 FADH2

Once again.. Citric Acid Cycle

One cycle of this pathway results results in 3 NADH and 1 FADH2 molecules
These molecules are essentially carriers of potential energy in the form of electrons
They will “donate” these electrons in the next step, called the electron transport chain

One molecule of glucose produces 38 ATP One 16C fatty acid produces 129 ATP!!!

Ketogenesis

Ketones are mainly produced by the liver, in the mitochondria
The process is considered to be glucose “sparing”
Two molecules of acetyl-CoA combine to produce acetoacetyl-CoA
A third acetyl-CoA is added to produce HMG-CoA
HMG-CoA drops two carbons to form Acetoacetate
Acetoacetate can be further converted to 𝞫-hydroxybutyrate
Acetone is expelled from the lungs as a gas

ketolysis

Almost the exact same reaction as ketosis in reverse
Ketones are converted BACK into acetyl-CoA and used in the TCA

Cholesterol metabolism

Synthesized in just about every cell of the body
- Kidney makes the dominant amount
- Very little dietary cholesterol is involved in serum cholesterol
Cholesterol circulates in the blood as a lipoprotein - bound to protein to become soluble
Cholesterol is the precursor molecule for ALL steroid hormones
- As such, the adrenal glands make a lot as well
- People with genetically low levels of blood cholesterol still have normal hormone levels
Plays a critical role in bile acid generation
Necessary for Vitamin D production
Finally, critical for cell membrane biology

Formation of Cholesterol

Very similar process to the formation of ketones, but occurs in the cytosol
The cytosol has a unique enzyme from the mitochondria, called HMG-CoA reductase that pushes the pathway towards cholesterol
Requires NADPH from the pentose phosphate pathway
T3, Insulin & high ATP levels stimulate this pathway
Cortisol (stress) and glucagon (low levels of glucose) inhibit

Phospholipids

Two fatty acids attached to a 3 carbon glycerol backbone with a “phosphodiester bridge”
- Most phospholipids have one saturated and on unsaturated fatty acid each
Phospholipids are characterized by the additions to these fatty acids
- Phosphatidylserine
- Phosphatidylethanolamine
- Phosphatidylcholine
- Phosphatidylinositol
- phosphatidylglycerols
Used to wrap all cells in the entire body
Involved in surfactants which are critical for lung function
Used in bile production as well, for detoxification

Eicosanoids

Otherwise known as Omega-6 and Omega-3 fatty acids
Derived from what we call “essential fatty acids” (linoleic acid and alpha linoleic acid)
Omega-6 can be processed to produce arachidonic acid, a pro-inflammatory molecule involved in innate immunity
Omega-3 can be processed to produce EPA and DHA, generally anti-inflammatory molecules

People are starting to say they are bad.. we typically have more Omega-6 in our diet which throws off the balance to Omega-3. The balance is important

Alpha linoleic acid is processed downstream to produce EPA and DHA
- anti-inflammatory
Linoleic acid is processed downstream to process arachidonic acid
Further processed to produce an array of inflammatory molecules

Omega-3 Mechanisms of Action

EPA and DHA signal through several membrane receptors to modulate pathways of inflammation and fibrosis

Dietary Fat

Stored fat can do Beta oxidation (produce acetyl-CoA) and Generate phospholipids but not produce omega-3/6 (you need them from diet!)

Summary

Lipids come in a diverse array of structures
Fats are digested by the combined action of bile and lipase enzymes
In energy rich states, dietary fats are stored as TAGs in adipose tissue
In energy poor states, dietary fats are used as an energy AND lipolysis occurs in adipose tissue, liberating fatty acids for energy use in the body
Fatty acids are broken down into Acetyl-CoA through a process called Beta-Oxidation
Ketones are created through the merging of 3 Acetyl-CoA molecules - Cholesterol is created from a very similar pathway
Phospholipids are similar to triglycerides, except they have replaced one fatty acid with a hydrophilic phosphodiester group
Omega-3 and 6 eicosanoids come almost exclusively from our diet and modify the inflammatory pathway