Lipid Metabolism Flashcards

Ketogenesis

  • Ketogenesis is a normal part of adaptive metabolism.
  • Involves the generation of ketone bodies.
  • Three main ketone bodies:
    • Acetoacetic Acid
    • 3-Hydroxybutyric Acid
    • Acetone (like nail polish remover)
  • All formed from Acetyl CoA.
  • Occurs when there's an excess of acetyl CoA production that cannot be processed by the citric acid cycle.
  • Ketone bodies are water-soluble and can be distributed in circulation.

Ketone Production

  • Two molecules of acetyl CoA condense to form Acetoacetyl CoA.
  • Acetoacetyl CoA is a precursor to acetoacetic acid (a ketone).
  • Acetoacetic acid can be modified to form 3-hydroxybutyric acid and acetone.
  • Ketones are synthesized in the mitochondria.
  • They are transported out across the mitochondrial membrane and into circulation.
  • The liver is a common site of synthesis.
  • Ketones can be exported to other tissues.

Ketone Body Oxidation

  • Ketone bodies can be readily oxidized back to acetyl CoA.
  • Acetoacetate, 3-hydroxybutyric acid, and acetone can be converted back into acetoacetic acid and then acetyl CoA, releasing two molecules of acetyl CoA.
  • This process can occur in different locations, like muscle tissue utilizing ketone bodies synthesized in the liver for energy (source of Acetyl CoA).

Succinyl CoA

  • Succinyl CoA/Succinate interrelationship with citric acid cycle.
  • When the citric acid cycle is highly active, conversion back to acetyl CoA occurs, which serves as a substrate for the cycle.

Circumstances Affecting Ketogenesis

  • Acetyl CoA is produced from the breakdown of fatty acids.
  • The activity of the citric acid cycle determines whether acetyl CoA enters the cycle or contributes to ketogenesis.
  • Indirectly Oxaloacetate concentration is the major determinant of the activity of the citric acid cycle.
  • Low concentrations of oxaloacetate may lead to the diversion of acetyl groups to ketogenesis.
Oxaloacetate Concentrations
  • Fasting animals: Oxaloacetate is used as a substrate for gluconeogenesis, lowering its concentration for the citric acid cycle.
  • Low carbohydrate diets: Same reason as above, to maintain blood glucose.
Ketones as a Marker
  • Ketones are a marker for starvation or negative energy balance.
  • Ketotic diets restrict carbohydrates to mobilize lipids and proteins, increasing ketone levels.
  • Normal ketone levels between meals are not a concern; they indicate adaptive metabolism.
  • Prolonged starvation or increased glucose demands can lead to significant ketone production, causing acidosis.

Biosynthesis of Lipids

  • Focus on triacylglycerols and phospholipids.

  • Common precursors:

    • Glycerol-3-phosphate (component of triacylglycerols and phospholipids)
    • Fatty acyl CoA (activated fatty acids)
Common Pathway

  • Glycerol-3-phosphate + two fatty acids -> diacylglycerol

  • Difference between triacylglycerols and phospholipids:

    • Triacylglycerols: Addition of another fatty acid.
    • Phospholipids: Addition of a polar head group.

  • Glycerol phosphate + two fatty acids creates diacylglycerol

  • Triacylglycerol synthesis: Diacylglycerol + another fatty acid -> triacylglycerol

  • Phospholipid synthesis: Diacylglycerol + polar head group -> phospholipid

Sphingolipids

  • Polar head group, one fatty acid, and a hydrocarbon tail from sphingosine.

    • Sphingosine synthesis: Palmitoyl CoA + serine (amino acid) -> sphingosine.

Steroids/Sterols

  • Cholesterol is a structure, and steroid hormones are modifications of cholesterol.
  • Formed from acetyl groups (acetyl CoA).

Isopentanyl Pyrophosphate

  • Intermediate in cholesterol synthesis, also important for other molecules like fat-soluble vitamins and carotenoids.
  • Carotenoids are colored molecules found in carrots and grasses; lipid soluble.

Ketoacidosis

  • Excessive acetyl CoA leads to temporary storage as ketone bodies.
  • Ketones distributed in circulation, taken up by tissues, and converted back to acetyl CoA.
  • Muscle cells reduce glucose use and increase ketone use during starvation.
  • Ketones acidic in nature (beta-hydroxybutyric acid, acetoacetic acid).
  • Excessive ketones can lower pH.

Physiological Circumstances

Starvation
  • Mobilization of lipids leading to ketoacidosis (fasting ketoacidosis).
Untreated Diabetes (Type 1)
  • Glucose lost in urine, leading to mobilization of body reserves including lipids to create ketoacidosis (diabetic ketoacidosis/ketosis).
  • Increased glucose demands
Lactating Dairy Cow (Peak Lactation)
  • High energy use for lactation causes negative energy balance from using body reserves.
  • Can lead to ketoacidosis.
    • 80%80\% of cows in highly productive dairy herds are bordering on ketoacidosis at peak lactation.
Sheep During Pregnancy (Multiple Offspring)
  • Limited nutrition + increased glucose demands from pregnancy causes ketoacidosis (ovine pregnancy toxemia).
Post-Exercise (Prolonged Exercise)
  • Mobilization of fat leads to potential ketoacidosis in animals like horses.

Clinical Signs

  • Animals appear immobile.
  • Loss of appetite.
  • Sharp reduction in milk production in cows.
  • Acetone smell (nail polish remover) in breath/milk/meat.
  • Diarrhea, Salivation (due to bicarbonate in saliva neutralizing acid).
  • Blindness (neurological impairment due to pH change).
  • Recumbency, Coma, Death (if untreated).

Treatment

  • Administer glucose (drip for quick energy).
  • Administer bicarbonate (to neutralize pH).

Ruminants and Ketoacidosis

  • Ruminants predisposed to metabolic ketoacidosis.

  • Cellulose broken down by bacteria in the rumen produces:

    • Propionate used as a substrate for gluconeogenesis.
    • Butyrate and Acetate forms Acetyl CoA as well.

  • Volatile fatty acids (VFAs) are ketogenic.