Lipid and Nitrogen Metabolism: Pathways and Regulation

Posted on Jan 27, 2025 in Human Nutrition and Dietetics

Saponifiable and Unsaponifiable Lipids

Saponifiable lipids are hydrolyzed under basic conditions and include:

  • Fatty acids
  • Acylglycerols
  • Phosphoglycerides
  • Sphingolipids
  • Waxes

Unsaponifiable lipids do not contain fatty acids in their structure. These include:

  • Terpenes
  • Steroids
  • Eicosanoids

Complex and Simple Lipids

Complex lipids are hydrolyzed into various components, such as:

  • Acylglycerides
  • Phosphoglycerides
  • Sphingolipids
  • Waxes

Simple lipids consist of one structural unit:

  • Fatty acids
  • Terpenoids
  • Eicosanoids
  • Steroids

Lipoprotein Metabolism

Exogenous Pathway: Metabolism of Chylomicrons

Chylomicrons absorb lipids from the diet and transport them through the lymphatic system.

  • Contain B48 and A Apolipoproteins.
  • Become functional by adding CII through an exchange with HDL.
  • Recognized by Lipoprotein Lipase.
  • Chylomicron Remnant: Richer in esterified cholesterol and smaller in size.
  • Discoidal portion esterified by LCAT and stored in HDL.
  • Remnant captured by the BE Receptor, and lipids are released in the liver.

Endogenous Pathway: Metabolism of VLDL, IDL, LDL

  • Endogenous cholesterol (EC) is packaged in VLDL and sent to the blood.
  • VLDL: APO B100 in the membrane is recognized by the LDL receptor.
  • Activation of VLDL occurs through lipid exchanges with HDL, adding C and E apolipoproteins (mature VLDL is recognized by lipoprotein lipase via APO CII).
  • VLDL is reshaped, and LCAT esterifies and reloads HDL.
  • Formation of IDL (containing cholesterol, APO B100, E, and C).
  • IDL to LDL interconversion with HDL.
  • LDL is captured by the liver via the LDL B/E receptor, releasing cholesterol into organs (esterification by ACAT, inhibition of HMG-CoA reductase).
  • Oxidized LDL is captured by macrophages (via scavenger receptors), leading to atherosclerotic plaque formation.

Reverse Cholesterol Transport: HDL Metabolism

  • Excess cholesterol in tissues is packaged into HDL and sent to the liver.
  • HDL matures through interconversion with IDL (donating esterified cholesterol and receiving free cholesterol). This reaction is catalyzed by LTP.
  • LCAT esterifies cholesterol from IDL.
  • HDL delivers cholesterol to the liver and participates in the maturation of VLDL and chylomicrons.

Energy Production from Lipids

Lipids stored in adipose tissue as triglycerides (TG) are broken down into fatty acids (FA) and glycerol.

  • Occurs under fasting conditions (glucagon, epinephrine). FA binds to albumin for transport.
  • TG Lipase (hormonally controlled, activated by phosphorylation) breaks down C1 and C3 bonds. MG Lipase breaks the C2 bond, releasing glycerol.
  • Preparation stage: Fatty acid activation by CoA to form Acyl-CoA (Acyl-CoA Synthetase). ATP is hydrolyzed to AMP.
  • Carnitine traps Acyl-CoA in the intermembrane space and binds it (Carnitine Acyl Transferase I) to form Acylcarnitine.
  • Translocase moves Acylcarnitine across the membrane. CAT II retrieves Acyl-CoA in the matrix.
  • Beta-Oxidation:
    • Acyl-CoA undergoes oxidation to generate a double bond (Acyl-CoA Dehydrogenase).
    • Hydration creates an -OH group and breaks the double bond (Enoyl-CoA Hydratase).
    • Oxidation of the -OH group to a ketone (Hydroxyacyl-CoA Dehydrogenase, requiring NAD+).
    • Thiolysis: CoA breaks the molecule, yielding Acetyl-CoA and a 2-carbon shorter Acyl-CoA (Ketothiolase). This process generates 5 ATP.
  • Unsaturated Fatty Acids: Isomerase moves the double bond between alpha and beta carbons. Epimerase converts D-isomers to L-isomers (only trans (L) isomers can be hydrolyzed).
  • Odd-Numbered Saturated Fatty Acids: Propionyl-CoA is converted to Succinyl-CoA (Propionyl-CoA Carboxylase, requiring biotin).
  • Peroxisomal Beta-Oxidation: Shortens fatty acids. Similar reactions occur, but NADH and FADH2 are dissipated as heat. FADH2 oxidation produces reactive oxygen species (ROS) that are neutralized by Catalase. Electrons are released to O2.

Fasting conditions lead to the inhibition of glycolysis, activation of gluconeogenesis, depletion of the citric acid cycle intermediates, activation of lipolysis, accumulation of Acetyl-CoA, and formation of ketone bodies.

Ketone Body Formation

Two molecules of Acetyl-CoA combine (catalyzed by Ketothiolase) to form Acetoacetyl-CoA. Acetoacetyl-CoA reacts with another Acetyl-CoA (catalyzed by HMG-CoA Synthase) to form Hydroxymethylglutaryl-CoA (HMG-CoA). HMG-CoA is converted to Acetoacetate (catalyzed by HMG-CoA Lyase), releasing Acetyl-CoA. Acetoacetate can undergo decarboxylation to form Acetone or be reduced to Beta-Hydroxybutyrate (catalyzed by a dehydrogenase, which is not a ketone).

Fatty Acid Biosynthesis (Lipogenesis)

Acetyl-CoA is converted to fatty acids and glycerol, which combine to form triglycerides (TG). This occurs when there is a scarcity of fatty acids and an excess of Acetyl-CoA.

  1. Transport of Acetyl-CoA to the Cytosol: Acetyl-CoA combines with Oxaloacetate to form Citrate (Citrate Synthase). Citrate is transported to the cytosol, where Citrate Lyase converts it back to Oxaloacetate and Acetyl-CoA. Oxaloacetate can be converted to Malate or Pyruvate and returned to the mitochondria.
  2. Activation of Precursor: Acetyl-CoA is converted to Malonyl-CoA (Acetyl-CoA Carboxylase, requiring biotin). This step is activated by polymerization and decarboxylation.
  3. Fatty Acid Synthase: The first 2-carbon fragment comes from Acetyl-CoA, and subsequent 3-carbon units come from Malonyl-CoA. The process involves condensation (to remove an extra carbon), reduction, dehydration, and reduction. The final products are Palmitic acid or Palmitoyl-CoA.
  • Microsomal Elongation: Uses Malonyl-CoA.
  • Mitochondrial Elongation: Uses Acetyl-CoA.
  • Microsomal Desaturation: Addition of double bonds. The electron transport chain (ETC) provides electrons from O2 and NADH.

Triglyceride Biosynthesis

Phosphatidic acid or 2-Monoacylglycerol is converted to 1,2-Diacylglycerol, which is then converted to Triacylglycerol (catalyzed by Diacylglycerol Acyltransferase).

  • In the absence of nitrogen, glycerol is activated.
  • In the presence of nitrogen, the polar group (e.g., ethanolamine) is activated.

A picture containing text, map Description automatically generated

Eicosanoids are derived from Arachidonic acid.

Cholesterol Metabolism

Occurs when there is high energy and sufficient substrate.

  1. Formation of Mevalonate from Acetyl-CoA: Two molecules of Acetyl-CoA condense to form Acetoacetyl-CoA. A third molecule of Acetyl-CoA is added to form HMG-CoA. HMG-CoA is converted to Mevalonate (catalyzed by HMG-CoA Reductase).
  2. Mevalonate to Squalene: Mevalonate is converted to Squalene through a series of reactions involving ATP and kinases.
  3. Squalene to Cholesterol: Squalene is cyclized by cyclases to form Cholesterol. This process requires O2 and reducing power (NADPH).

Regulation of Cholesterol Synthesis

  • Long-Term Regulation: Insulin increases HMG-CoA Reductase levels, promoting cholesterol synthesis.
  • Short-Term Regulation: HMG-CoA Reductase is active when dephosphorylated. During fasting, AMP-activated protein kinase (AMPK) is active, leading to phosphorylation and inactivation of HMG-CoA Reductase.

Cholesterol can be transformed into bile acids.

Nitrogen Metabolism

Nitrogen-containing compounds serve as precursors for proteins, peptides, and other nitrogenous compounds, as well as metabolic fuels.

Digestion and Absorption

Zymogens (e.g., Pepsinogen) are secreted and converted to their active forms (e.g., Pepsin). Endopeptidases and Exopeptidases are secreted in the pancreas. Proteins are broken down into oligopeptides (by aminopeptidases), then into tripeptides (by peptidases), and finally into amino acids that are absorbed into the bloodstream.

Amino Acid Metabolism

Amino acids are used in ribosomal protein synthesis or derived from endogenous protein breakdown via proteolysis (involving the proteasome and ubiquitin).

  • Transamination: Amino Acid 1 + Alpha-Ketoglutarate are converted to Glutamate + Ketoacid 2 (catalyzed by Aminotransferase).
  • Oxidative Deamination: Glutamate is converted to Alpha-Ketoglutarate and Ammonium (NH4+) (catalyzed by Glutamate Dehydrogenase).
  • Ammonium is transported via the Glutamate-Glutamine cycle.

Urea Cycle

  1. First Nitrogen Atom Uptake (Mitochondria): CO2 + NH4+ are converted to Carbamoyl Phosphate (catalyzed by Carbamoyl Phosphate Synthetase I). This is the limiting step.
  2. Start of the Cycle; Citrulline Production: Carbamoyl Phosphate + Ornithine are converted to Citrulline (catalyzed by Ornithine Transcarbamylase).
  3. Second Nitrogen Atom Uptake (Cytosol): Aspartate + Citrulline are converted to Argininosuccinate (catalyzed by Argininosuccinate Synthetase, requiring 2 ATP).
  4. Argininosuccinate Breakdown: Argininosuccinate is broken down into Fumarate (which enters the citric acid cycle for the synthesis of Aspartate) and Arginine (catalyzed by Argininosuccinate Lyase).
  5. Urea Release and Ornithine Regeneration: Arginine is converted to Ornithine (catalyzed by Arginase). The imide form of urea is converted to urea for excretion.

The urea cycle is initiated by the activation of Carbamoyl Phosphate Synthetase I by allosteric activators.

A picture containing text, map Description automatically generated