Lipid Metabolism and Ketogenesis

Ketogenesis

Ketogenesis is a normal part of adaptive metabolism.
Involves the generation of ketone bodies: Acetoacetic Acid, 3-Hydroxybutyric Acid, and Acetone.
Acetone is a ketone body (like nail polish remover).
All ketone bodies are formed from Acetyl CoA when there's an excess of acetyl CoA production.
Ketones are water-soluble and can be distributed in circulation to be taken up by other tissues.
Two molecules of acetyl CoA condense to form Acetoacetyl CoA, which is a precursor to other ketone bodies.

Ketones are synthesized in the mitochondria, transported across the mitochondrial membrane, and moved out of cells into circulation.
The liver is a common site of synthesis, but ketones can be exported to other tissues.
Ketone bodies are readily oxidized back to acetyl CoA.
- Acetoacetate, 3-hydroxybutyric acid, and acetone can be converted back to acetoacetic acid, and then back to two molecules of acetyl CoA.
This allows for the distribution of energy (acetyl CoA) to different locations (e.g., from liver to muscle tissue).
Succinyl CoA is related to the citric acid cycle, suggesting an interrelationship between these processes.

Acetyl CoA is produced from the breakdown of fatty acids.
The major determinant is the activity of the citric acid cycle and the concentration of oxaloacetate.
High oxaloacetate concentrations lead to oxidation through the citric acid cycle.
Low oxaloacetate concentrations divert acetyl groups to ketogenesis.
Lower oxoacetate concentrations are seen in fasting animals due to gluconeogenesis.
Ketones are a marker for starvation or negative energy balance.
- Normal amounts of ketones between meals are normal and indicate adaptive metabolism.
Ketotic diets restrict carbohydrate to mobilize lipid and protein, increasing ketone production.
Prolonged starvation or increased glucose demands can lead to excessive ketone production, causing acidosis.

Triacylglycerols and phospholipids share common pathways and precursors:
- Glycerol-3-phosphate
- Fatty acyl CoA (activated fatty acids)
Glycerol-3-phosphate comes from dihydroxyacetone phosphate (an intermediate in glycolysis/gluconeogenesis).

Start with glycerol-3-phosphate.
Add two fatty acids to form diacylglycerol.
The difference lies in the addition of a third fatty acid (for triacylglycerols) or a polar head group (for phospholipids).
The biosynthesis pathways for tricyclicals and phospholipids are simple and diverge at the last step.

Have a polar head group and one fatty acid; the other hydrocarbon tail comes from sphingosine.
Sphingosine synthesis involves condensation between serine and palmitoyl CoA (a C16 fatty acid).

Cholesterol is the base structure, and steroid hormones are modifications of cholesterol.
Complex ring structures are formed from many acetyl groups (from acetyl CoA).
Isopentanyl pyrophosphate is an intermediate in cholesterol synthesis and is also important for synthesizing fat-soluble vitamins like carotenoids.

Ketogenesis is a temporary storage mechanism for excess acetyl CoA as ketone bodies, which can be distributed and used by other tissues.
Muscle cells may decrease glucose use and increase ketone use during starvation.
Ketones serve as an indirect measure of energy balance.

Fasting ketoacidosis: due to fasting and mobilization of tissue.
Diabetic ketoacidosis: due to glucose not entering cells and loss in urine, leading to mobilization of body reserves.
Bovine ketosis: in lactating dairy cows at peak lactation, where energy demands exceed intake.
Ovine pregnancy toxemia: in pregnant sheep with multiple offspring, due to increased glucose demands and limited nutrition.
Post-exercise ketoacidosis: in animals after prolonged exercise due to fat mobilization.

Animals appear immobile.
Loss of appetite.
Sharp reduction in milk production (cows).
Acetone smell (like nail polish remover) in breath, milk, or meat.
Diarrhea and salivation (due to acid elimination and neurological response to acid).
Neurological impairment.
Recumbency, coma, and death.

Ruminants are predisposed due to their carbohydrate metabolism.
Bacteria in the rumen produce propionate, lactate, butyrate, and acetate from cellulose.
Propionate can be used for gluconeogenesis, while acetate and butyrate break down into acetyl CoA.
Volatile fatty acids (VFAs) from bacterial metabolism are ketogenic.