Metabolism of Triacylglycerols

TAGs Overview & Digestion - TAG Team Intro

• Structure: Glycerol + 3 FAs (ester bonds); hydrophobic, energy store.
• Dietary Digestion:
  • Mouth: Lingual lipase (minor).
  • Stomach: Gastric lipase (minor; key in infants).
  • Small Intestine: Pancreatic lipase (major) + Colipase. Hydrolyzes $sn-1, sn-3 \rightarrow$ 2-MAG + FFAs.
• Bile Salts: Emulsify fats $\rightarrow$ micelles; $\uparrow$ surface area for lipase.
• Absorption (Enterocytes):
  • 2-MAG & long-chain FFAs absorbed.
  • Short/medium-chain FAs $\rightarrow$ portal blood.
• Re-synthesis & Transport:
  • In enterocytes: 2-MAG + FFAs $\rightarrow$ TAGs.
  • TAGs + Apo B-48 $\rightarrow$ Chylomicrons.
  • Chylomicrons $\rightarrow$ Lymph (lacteals) $\rightarrow$ Blood.

⭐ Apo B-48 is exclusively found in chylomicrons, distinguishing them from VLDL (which contains Apo B-100).

TAG Synthesis (Lipogenesis) - Fat Factory Fun

• Primary Sites: Liver, adipose tissue, lactating mammary glands, intestinal mucosa.

• Substrates: Glycerol-3-Phosphate (G3P), Fatty Acyl-CoA.

• G3P Sources:

  • Liver/Kidney: Glycerol $\xrightarrow{\text{Glycerol Kinase}}$ G3P.
  • Liver/Adipose: DHAP (Glycolysis) $\xrightarrow{\text{Glycerol-3-P Dehydrogenase}}$ G3P.

• FA Activation: Fatty Acid + CoA + ATP $\xrightarrow{\text{Acyl-CoA Synthetase (Thiokinase)}}$ Fatty Acyl-CoA.

• Pathway: 📌 "Good Apples Pay Dearly" (GPAT, AGPAT, PAP, DGAT)

  • Enzymes: Glycerol-3-phosphate acyltransferase (GPAT), Acylglycerophosphate acyltransferase (AGPAT), Phosphatidic acid phosphatase (PAP/Lipin), Diacylglycerol acyltransferase (DGAT).

• Regulation: Insulin ↑ TAG synthesis (induces GPAT, DGAT; ↑ glucose for G3P & FA).

• Export: Liver TAGs → VLDL (ApoB-100). synthesis)

⭐ Phosphatidic acid phosphatase (PAP/Lipin) is a pivotal regulatory enzyme, converting PA to DAG, a committed step.

TAG Mobilization (Lipolysis) - Energy Release Party

• Site: Adipose tissue (stored TAGs).
• Process: TAGs $\rightarrow$ FFAs + Glycerol.
• Key Enzymes:
  • ATGL (Adipose Triglyceride Lipase): TAG $\rightarrow$ DAG + FFA.
  • HSL (Hormone-Sensitive Lipase): DAG $\rightarrow$ MAG + FFA (Rate-limiting; PKA-activated).
  • MGL (Monoacylglycerol Lipase): MAG $\rightarrow$ Glycerol + FFA.
• Hormonal Regulation:
  • Stimulators (↑cAMP/PKA): Catecholamines (Epinephrine, Norepinephrine), Glucagon, ACTH $\rightarrow$ ↑HSL & Perilipin activity (phosphorylation).
  • Inhibitor (↓cAMP): Insulin $\rightarrow$ ↓HSL activity (promotes dephosphorylation via phosphodiesterase & phosphatase activation).

• Fate:
  • Glycerol: To liver (requires Glycerol Kinase) $\rightarrow$ Glycerol-3-Phosphate ($G3P$) $\rightarrow$ Glycolysis / Gluconeogenesis. (Adipocytes lack glycerol kinase).
  • FFAs: Blood (albumin-bound) $\rightarrow$ Tissues (e.g., muscle for $\beta$-oxidation $\rightarrow ATP$) or Liver (ketogenesis during prolonged fasting).

⭐ HSL is the main hormonally regulated enzyme in lipolysis. Activated by phosphorylation (via PKA from Glucagon/Epinephrine); inactivated by dephosphorylation (via phosphatase, promoted by Insulin).

TAG Clinical Correlations - Lipid Trouble Spots

• Hypertriglyceridemia: ↑ Fasting TAGs.
  • Levels (mg/dL): Normal <150; Borderline 150-199; High 200-499; Very High ≥500.
  • Causes:
    • Primary: Genetic (e.g., LPL/ApoC-II deficiency).
    • Secondary: Obesity, Type 2 Diabetes, metabolic syndrome, alcohol, hypothyroidism, drugs.
  • Significance: Risk for pancreatitis (esp. TAGs >1000 mg/dL), cardiovascular disease.
• LPL/Apo C-II Deficiency (Type I Hyperlipoproteinemia):
  • Massive fasting chylomicronemia.
  • Features: Eruptive xanthomas, hepatosplenomegaly, recurrent pancreatitis.
  • No increased atherosclerosis risk.

  ⭐ In LPL or ApoC-II deficiency (Type I Hyperlipoproteinemia), despite massive chylomicronemia and pancreatitis risk, atherosclerosis risk is NOT typically increased.

• Fatty Liver Disease (Steatosis): TAG accumulation in hepatocytes.
  • Non-alcoholic fatty liver disease (NAFLD): Assoc. with insulin resistance, obesity.
  • Alcoholic fatty liver disease (AFLD): Due to alcohol.

High‑Yield Points - ⚡ Biggest Takeaways

• HSL (activated: glucagon/epinephrine; inhibited: insulin) mobilizes stored TAGs.
• LPL (activated: Apo C-II) clears TAGs from chylomicrons/VLDL for tissue uptake.
• Glycerol from TAGs fuels hepatic gluconeogenesis or glycolysis.
• Mitochondrial β-oxidation of fatty acids yields Acetyl-CoA, NADH, FADH2.
• Carnitine shuttle (CPT-I is rate-limiting, inhibited by Malonyl-CoA) transports LCFAs into mitochondria.
• TAGs are synthesized from glycerol-3-P & fatty acyl-CoAs in liver/adipose tissue.
• Insulin promotes TAG storage and inhibits lipolysis.