Fatty Acids and Triacylglycerols Notes

Fatty Acids

Described by total carbon number:number of double bonds (e.g., carbons:double bonds).
Further description includes position and isomerism of double bonds.
Saturated fatty acids: no double bonds.
Unsaturated fatty acids: one or more double bonds.
Humans can only synthesize some unsaturated fatty acids; others are essential fatty acids from the diet, transported in chylomicrons as triacylglycerols.
Two important essential fatty acids: alpha-linolenic acid and linoleic acid.
These polyunsaturated fatty acids maintain cell membrane fluidity, crucial for cell function.
Omega numbering system: describes the position of the last double bond relative to the end of the chain.
- Identifies the major precursor fatty acid.
- Example: Linoleic acid (18:2 cis, cis-9,12) is the precursor of the omega-6 family, which includes arachidonic acid.
- Alpha-linolenic acid (18:3 all-cis-9,12,15) is the primary precursor of the omega-3 family.
Double bonds in natural fatty acids are generally in the cis configuration.

Fatty acids for fuel primarily from diet.
Excess carbohydrates and proteins can be converted to fatty acids and stored as triacylglycerols.
Lipid and carbohydrate synthesis are non-template synthesis processes (do not rely on nucleic acid coding).

Occurs in the liver; products transported to adipose tissue for storage.
Adipose tissue can also synthesize fatty acids in smaller quantities.
Major enzymes: acetyl-CoA carboxylase and fatty acid synthase, both stimulated by insulin.
Palmitic acid (palmitate) is the primary end product.

Following a large meal, acetyl-CoA accumulates in the mitochondrial matrix.
Needs to be moved to the cytosol for fatty acid biosynthesis.
Acetyl-CoA (product of pyruvate dehydrogenase complex) + oxaloacetate → citrate (beginning of citric acid cycle).
Isocitrate dehydrogenase is the rate-limiting enzyme of the citric acid cycle. When the cell is energetically satisfied, the cycle slows, causing citrate accumulation.
Citrate diffuses across the mitochondrial membrane; in the cytosol, citrate lyase splits it back into acetyl-CoA and oxaloacetate.
Oxaloacetate returns to the mitochondrion to continue moving acetyl-CoA.

Acetyl-CoA is activated in the cytoplasm by acetyl-CoA carboxylase (rate-limiting enzyme of fatty acid biosynthesis).
Requires biotin and ATP to function.
Adds CO_2 to acetyl-CoA to form malonyl-CoA.
Activated by insulin and citrate.
The added CO_2 is not incorporated into the fatty acid; it's removed by fatty acid synthase.

Palmitate synthase (palmitate is the only fatty acid humans can synthesize de novo).
Large multi-enzyme complex in the cytosol; rapidly induced in the liver after a high-carbohydrate meal due to elevated insulin.
Contains an acetyl carrier protein (ACP) that requires pantothenic acid (vitamin B5).
NADPH is required to reduce the acetyl groups added.
8 acetyl-CoA groups are required to produce palmitate (16:0).
Fatty acyl-CoA may be elongated and desaturated (to a limited extent) using enzymes associated with the smooth endoplasmic reticulum (SER).
Steps:
- Attachment to acetyl carrier protein (ACP).
- Bond formation between activated malonyl-CoA (malonyl-ACP) and the growing chain.
- Reduction of carbonyl group.
- Dehydration.
- Reduction of a double bond.
Reactions repeat until 16-carbon palmitate is created.
Many reactions are reversed in beta-oxidation.

Storage form of fatty acids; formed by attaching three fatty acids (as fatty acyl-CoA) to glycerol.
Formation from fatty acids and glycerol-3-phosphate occurs primarily in the liver and (somewhat) in adipose tissue; small contribution directly from the diet as well.
In the liver, triacylglycerols are packaged and sent to adipose tissue as very-low-density lipoproteins (VLDL), leaving only a small amount of stored triacylglycerols.

Most fatty acid catabolism proceeds via beta-oxidation (occurs in the mitochondria).
Peroxisomal beta-oxidation also occurs.
Branched-chain fatty acids may undergo alpha-oxidation (depending on branch points), while omega-oxidation in the endoplasmic reticulum produces dicarboxylic acids.
Insulin indirectly inhibits beta-oxidation, while glucagon stimulates it.

Short-chain (2-4 carbons) and medium-chain (6-12 carbons) fatty acids diffuse freely into mitochondria.
Long-chain fatty acids (14-20 carbons) require transport via the carnitine shuttle.
Carnitine acyltransferase I is the rate-limiting enzyme of fatty acid oxidation.
Very long-chain fatty acids (over 20 carbons) are oxidized elsewhere in the cell.

Reverses fatty acid synthesis by oxidizing and releasing acetyl-CoA molecules.
Four-step cycle:
- Releases one acetyl-CoA.
- Reduces NAD^+ and FAD, producing NADH and FADH2. FADH2 and NADH are oxidized in the electron transport chain, producing ATP.
In muscle and adipose tissue, acetyl-CoA enters the citric acid cycle.
In the liver, acetyl-CoA (which cannot be converted to glucose) stimulates gluconeogenesis by activating pyruvate carboxylase.
In a fasted state, the liver produces more acetyl-CoA from beta-oxidation than is used in the citric acid cycle.
Excess acetyl-CoA is used to synthesize ketone bodies, which are released into the bloodstream and transported to other tissues.
Four steps of beta-oxidation:
1. Oxidation of the fatty acid to form a double bond.
2. Hydration of the double bond to form a hydroxyl group.
3. Oxidation of the hydroxyl group to form a carbonyl (beta-keto acid).
4. Splitting of the beta-keto acid into a shorter acyl-CoA and acetyl-CoA.
Process continues until the chain is shortened to two carbons, creating a final acetyl-CoA.

Undergo beta-oxidation similarly to even-numbered fatty acids.
During the final cycle:
- Even-numbered fatty acids yield two acetyl-CoA molecules from the four-carbon fragment.
- Odd-numbered fatty acids yield one acetyl-CoA and one propanoyl-CoA from the five-carbon fragment.
Propanoyl-CoA is converted to methylmalonyl-CoA by propanoyl-CoA carboxylase (requires biotin/vitamin B7).
Methylmalonyl-CoA is converted into succinyl-CoA by methylmalonyl-CoA mutase (requires cobalamin/vitamin B12).
Succinyl-CoA (citric acid cycle intermediate) can be converted to malate to enter the gluconeogenic pathway.
Odd-carbon fatty acids represent an exception to the rule that fatty acids cannot be converted to glucose in humans.

Require two additional enzymes because double bonds disturb the stereochemistry.
Enzymes can have at most one double bond in their active site, located between carbons 2 and 3.
Enoyl-CoA isomerase rearranges cis double bonds at the 3,4 position to trans double bonds at the 2,3 position.
In monounsaturated fatty acids, this single set permits beta-oxidation to proceed.
In polyunsaturated fatty acids, a further reduction is required using 2,4-dienoyl-CoA reductase to convert two conjugated double bonds to just one double bond at the 3,4 position, where it will then undergo the same rearrangement as monounsaturated fatty acids to form a trans-2,3 double bond.