Metabolism of Lipids: Ketogenesis, Fatty Acid Synthesis, and More

Ketogenesis

  • Occurs in the liver mitochondrial matrix.
  • Involves the biosynthesis of ketone bodies from Acetyl-CoA.
  • Key steps:
    • Acetyl-CoA is converted to HMG-CoA by HMG-CoA synthase.
    • HMG-CoA is then cleaved by HMG-CoA lyase to Acetoacetate.
    • Acetoacetate can be reduced to \$\beta\$-Hydroxybutyrate or spontaneously decarboxylated to Acetone.
  • Enzymes involved: HMG-CoA synthase, HMG-CoA lyase, \$\beta\$-Hydroxybutyrate dehydrogenase, and \$\beta\$-Ketothiolase.

TCA Cycle and Gluconeogenesis

  • TCA Cycle: Acetyl-CoA from glucose metabolism enters the cycle, producing NADH, FADH2, and ATP.
  • Gluconeogenesis: Pyruvate is converted to glucose, utilizing enzymes and intermediates.

Fatty Acid Synthesis

  • Occurs in the cytosol.
  • Early studies highlighted the requirement for bicarbonate and malonyl CoA.
  • Acetyl-CoA, derived from both fat and carbohydrate breakdown, is a major fat precursor.
  • Involves the synthesis of malonyl-CoA (carboxylation of acetyl-CoA).
  • Process: Condensation, Reduction, Dehydration, and Reduction.
  • Requires Acetyl-CoA carboxylase (ACC) for malonyl-CoA synthesis.
  • ACP (Acyl Carrier Protein) contains phosphopantetheine as the reactive unit.
  • Fatty acid synthase complex contains two identical multifunctional protein chains and a swinging arm of ACP.
  • Cycle involves condensation, reduction, dehydration and reduction to elongate fatty acid.
  • Transport of acetyl units and NADPH into the cytosol is crucial.

Fatty Acid Chain Elongation and Desaturation

  • Elongation occurs in both mitochondria and endoplasmic reticulum, involving condensation between malonyl-CoA and a long-chain fatty acyl-CoA.
  • Desaturation, a microsomal system, is catalyzed by fatty acyl-CoA desaturase.
  • Animals cannot introduce double bonds beyond C\$\Delta\$9.

Control of Fatty Acid Synthesis

  • Insulin promotes fatty acid synthesis.
  • Long-chain fatty acyl-CoA prevents the inactivation of acetyl-CoA carboxylase.
  • Citrate lyase is upregulated by insulin.
  • NADPH provides reducing equivalents.

Biosynthesis of Triacylglycerols

  • Glycerol-3-phosphate is acylated by acyltransferases to form triacylglycerols.
  • Key intermediates: Lysophosphatidic acid, phosphatidic acid, 1,2-diacylglycerol.

Glycerophospholipids

  • Most abundant phospholipids derived from glycerol, primarily found in membranes.
  • Metabolic precursors to regulatory elements in signal transduction pathways.
  • Involved in the transport of triacylglycerols and cholesterol.
  • Examples: Phosphatidic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin).

Phospholipids in Bacteria and Eukaryotes

  • In prokaryotes (e.g., E. coli), phospholipids constitute a significant portion of the cell's dry weight.
  • Eukaryotic cells contain six main classes of glycerophospholipids: PE, PG, CL, PS, PC, and PI.
  • Lung surfactant contains dipalmitophosphatidylcholine.

Sphingolipids

  • Based on a long-chain amino alcohol backbone instead of glycerol.
  • Important in nervous tissue.

Steroids and Isoprenoids

  • Isoprenoids (terpenes) are built from five-carbon units, including steroids, bile acids, and lipid-soluble vitamins.
  • Steroids are derivatives of perhydrocyclopentanophenanthrene, with cholesterol being a key example.
  • Cholesterol's rigid structure reduces membrane fluidity.

Cholesterol Biosynthesis

  • All carbons are derived from acetate.
  • Stages: Formation of mevalonate, synthesis of squalene, cyclization of squalene to lanosterol and conversion to cholesterol.
  • HMG-CoA reductase is the key regulatory enzyme.

Bile Acids and Steroid Hormones

  • Bile acids (e.g., cholic acid and chenodeoxycholic acid) emulsify dietary lipids.
  • Steroid hormones are derived from cholesterol, produced in gonads and adrenal cortex.
  • Major classes: progestins, glucocorticoids, mineralocorticoids, androgens, estrogens.

Eicosanoids

  • Include prostaglandins, thromboxanes, and leukotrienes, derived from arachidonic acid.
  • Act as local hormones with roles in inflammation, childbirth, allergy, asthma, and rheumatoid arthritis.
  • Inhibit platelet aggregation and relax coronary arteries.

Dietary Fat and Lipoproteins

  • Functions of dietary fat: energy, cell membranes, cell signaling.
  • Plasma lipoproteins have a hydrophobic core of triacylglycerol and cholesterol esters.
  • Chylomicrons are produced via the exogenous lipoprotein pathway.
  • Atherogenic Lipoprotein Phenotype (ALP) includes reduced HDL, small dense LDL, and raised triglycerides.

Metabolic Interconversions and Locations

  • Fatty acids can be made from but not converted to carbohydrates and amino acids.
  • Acetyl CoA, produced in the mitochondria, is transported into the cytosol via citrate for fatty acid synthesis.
  • The liver and intestines are the most active organs in triacylglycerol synthesis.
  • Fatty acid \$\beta\$-oxidation occurs in mitochondria and peroxisomes.
  • De novo fatty acid synthesis occurs in the cytosol.
  • Acetyl CoA carboxylase is allosterically regulated by fatty acids and citrate.