Lipid Metabolism Notes

Lipid Digestion and Absorption

  • Triglycerides (TAGs): 98% of ingested lipids.
  • Digestion in Stomach: Gastric lipase hydrolyzes ~10% of TAGs.
  • Digestion in Duodenum: Bile salts emulsify lipids, forming smaller droplets for easier digestion.
  • Pancreatic Lipase: Hydrolyzes emulsified fats into fatty acids and monoacylglycerol (MAG).
  • Micelles: Carry free fatty acids and MAG to intestinal epithelium for absorption.
  • Chylomicrons: Triglycerides are reformed in intestinal cells and packaged into chylomicrons for transport into the lymph system and then blood. Transport exogenous lipids.

Lipid Transport - Lipoproteins

  • Lipoproteins: Transport phospholipids, triglycerides, cholesterol, and cholesterol esters.
  • Classified by density (TAG proportion):
    • Chylomicrons: Transport dietary fats.
    • VLDL: Very low-density lipoproteins, transport endogenous fats.
    • IDL: Intermediate-density lipoproteins, LDL precursor.
    • LDL: Low-density lipoproteins, transport cholesterol.
    • HDL: High-density lipoproteins, reverse cholesterol transport ("good" cholesterol).
  • Structure: Non-polar lipid core (TAG, cholesterol esters) surrounded by a polar coat (phospholipids, free cholesterol, apolipoproteins).
  • Lipoprotein Lipase (LPL): Breaks down triacylglycerols in chylomicrons.
  • LDL: Delivers cholesterol from the liver to peripheral tissues via receptor-mediated endocytosis.
  • HDL: Transports cholesterol from tissues back to the liver.

Lipid Breakdown (Lipolysis)

  • Lipolysis: Breakdown of triacylglycerols into fatty acids and glycerol in adipocytes.
  • Hormone-Sensitive Lipase: Hydrolyzes triacylglycerol; activated by epinephrine and glucagon (via PKA), inhibited by insulin.
  • Fatty acids: Transported by serum albumin in the bloodstream.

Fatty Acid Activation and Transport into Mitochondria

  • Activation: Fatty acid + CoA + ATP --> acyl CoA + AMP + PPi (catalyzed by fatty acyl CoA synthetase).
    • Consumes 2 ATP.
  • Carnitine Shuttle: Transports acyl CoA into the mitochondrial matrix for β-oxidation.

β-Oxidation of Fatty Acids

  • Process: Sequential removal of 2-carbon acetyl CoA units from the carboxyl end of the acyl chain in mitochondria.
  • Products: Acetyl CoA, FADH2, NADH.
  • Location: Mitochondrial matrix.
  • Regulation: Hormonal and allosteric controls.

Energy Yield Calculation (Palmitate Example)

  • Palmitoyl-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7 H2O --> 8 Acetyl-CoA + 7 FADH2 + 7 NADH + 7 H+
  • 7 FADH2 --> 7 × 1.5 ATP = +10.5 ATP
  • 7 NADH --> 7 × 2.5 ATP = +17.5 ATP
  • 8 Acetyl-CoA --> TCA --> 8 × 10 ATP = +80 ATP
  • Activation = -2 ATP
  • Net ATP = 108 - 2 = 106 ATP

Fatty Acid Synthesis (Lipogenesis)

  • Location: Cytosol.
  • Requires: NADPH, ATP, biotin, and bicarbonate.
  • End Product: Palmitate (16:0).

Key Differences Between Lipogenesis and β-oxidation

FeatureLipogenesis (Synthesis)β-oxidation (Breakdown)
LocationCytosolMitochondria
Carbon SourceMalonyl CoAAcetyl CoA
Reductant/OxidantNADPHNAD+, FAD

Citric Acid Shuttle

  • Purpose: Transports acetyl CoA from mitochondria to cytosol.
  • Process: Acetyl CoA + oxaloacetate (OAA) --> citrate; citrate --> acetyl CoA + OAA (via ATP-citrate lyase).
  • NADPH Production: OAA --> malate --> pyruvate (by malic enzyme), generating NADPH.

Formation of Malonyl CoA

  • Reaction: Acetyl CoA + CO2 + ATP --> Malonyl CoA + ADP + Pi (catalyzed by acetyl CoA carboxylase (ACC)).

Regulation of Fatty Acid Synthesis

  • Acetyl CoA Carboxylase (ACC): Rate-limiting enzyme.
    • Activated by dephosphorylation (protein phosphatase 2A).
    • Inhibited by phosphorylation (AMP-dependent protein kinase (AMPK)).
  • Hormonal Regulation:
    • Insulin: Activates ACC.
    • Glucagon/Epinephrine: Inhibit ACC.

Ketone Bodies

  • Synthesis: In mitochondria of liver cells from acetyl CoA.
  • Purpose: Alternative fuel source during starvation, low-carb diets, or uncontrolled diabetes.
  • Types: Acetone, acetoacetate, β-hydroxybutyrate.
  • Usage: Used by the brain and other tissues.
  • Export: Water-soluble and transported to other tissue.
  • Conversion: Converted back to acetyl CoA for TCA cycle.
  • Liver: Lacks the converting enzyme (CoA transferase) and exports ketone bodies.

Ketone Body Production During Starvation

  • Gluconeogenesis Promotes Ketogenesis: Oxaloacetate (OAA) is depleted due to gluconeogenesis.
    • The lower the OAA molecules, acetyl CoA cannot enter TCA cycle. Acetyl CoA is thus diverted to ketogenesis.