Lipid Metabolism Overview

Overview of Lipid Metabolism

• Acetyl-CoA is a central molecule: It originates from pyruvate (glycolysis), amino acid catabolism, and fatty acid breakdown.
• Acetyl-CoA enters the TCA cycle (Krebs cycle) to produce reducing equivalents for the electron transport chain, generating ATP.
• Acetyl-CoA is a precursor for fatty acid and steroid synthesis.
• Excess dietary fat is stored as triacylglycerol in adipose tissue.
• Phospholipids are required for synthesizing cell membranes and various lipoproteins.
• Lipids contribute to synthesizing hormones like steroid hormones and eicosanoids.
• Lipid utilization varies depending on whether the body is in a well-fed or fasting state.

Major Metabolic Phases of Lipids

• Lipid metabolism is examined in two states: well-fed and fasting/starvation.
• Well-fed state:
  • Digestion and absorption of dietary lipids is the first major step.
  • De novo synthesis of fatty acids also occurs.
  • Fatty acids are stored as triacylglycerol (TAG) through lipogenesis.
  • Lipoprotein metabolism occurs via the metabolism of various lipoproteins (chylomicrons, VLDL, LDL, HDL) and their functions.
  • Cholesterol and compound lipid (phospholipids, glycolipids) synthesis also takes place.
• Fasting/Starvation:
  • Lipolysis breaks down stored triacylglycerol into fatty acids and glycerol.
  • Fatty acids undergo beta-oxidation and ketogenesis.
  • Ketone bodies are utilized by various tissues.
• Insulin governs the well-fed state.
• Glucagon and epinephrine govern the fasting/starvation state.

Localization of Major Metabolic Pathways within the Cell

• Fatty acid synthesis occurs in the cytosol.
• Cholesterol synthesis occurs in the cytosol and endoplasmic reticulum.
• Glycolysis occurs in the cytosol.
• Fatty acid activation happens in the endoplasmic reticulum and outer mitochondrial membrane.
• Fatty acid oxidation occurs in the mitochondria.
• Ketone body synthesis occurs in the mitochondria.
• Synthesis of triacylglycerol and phospholipids occurs on the smooth endoplasmic reticulum.

Overview of Lipid Metabolism Pathways

• Metabolic pathways occur in the cytosol and mitochondria.
• Acetyl-CoA is central and derived from pyruvate and amino acids.
• Acetyl-CoA can enter the TCA cycle or be directed to fatty acid synthesis.
• Fatty acid synthesis is favored in the well-fed state.
• Fatty acids are stored in adipose tissue as triacylglycerol, also derived from chylomicrons and VLDL.
• The glycerol backbone for triacylglycerol synthesis comes from dihydroxyacetone phosphate (DHAP).
• Triacylglycerol is stored in adipose tissue and used during fasting and starvation through lipolysis.
• Acetyl-CoA also serves as a precursor for cholesterol.
• During fasting and starvation, triacylglycerol is broken down via lipolysis into glycerol and fatty acids.
• Glycerol is converted to DHAP and can enter glycolysis or be used for gluconeogenesis.
• Fatty acids undergo beta-oxidation, producing acetyl-CoA.
• Increased beta-oxidation leads to increased acetyl-CoA, which can lead to ketone body synthesis during starvation.

Regulation of Major Metabolic Pathways

• Major metabolic pathways are regulated via:
  • Substrate availability
  • Allosteric regulation
  • Covalent modification
  • Induction or repression of enzyme synthesis
• Increased acetyl-CoA availability favors fatty acid synthesis.
• During fasting and starvation, fatty acid oxidation increases acetyl-CoA availability.
• Acetyl-CoA carboxylase (ACC) is a regulatory enzyme in fatty acid synthesis.
  • Citrate activates ACC, favoring fatty acid synthesis during the well-fed state.
• Insulin governs the well-fed state.
  • Insulin regulates enzyme activity through covalent modification and induction.
  • Insulin causes dephosphorylation of enzymes and activates several, including ACC.
• Hormone-sensitive lipase (HSL) is involved in lipolysis.
  • HSL is inactive when dephosphorylated.
  • Insulin promotes dephosphorylation and inactivation of HSL, inhibiting lipolysis.
• Induction of enzyme synthesis:
  • Insulin induces the synthesis of enzymes like ACC and HMG-CoA reductase (a rate-limiting enzyme in cholesterol synthesis).
• Glucagon governs the fasting state and opposes insulin's actions.
  • Glucagon promotes phosphorylation, activating HSL and stimulating lipolysis.
• Hormones regulate lipid metabolism through these mechanisms.

Action of Various Lipases in Lipid Metabolism

• Lingual and Gastric Lipases:
  • Site of action: Mouth and stomach
  • Hydrolyze triacylglycerol, particularly small and medium-chain fatty acids (important in infants)
  • Products: fatty acids and diacylglycerol
• Pancreatic Lipase:
  • Site of action: Duodenum
  • Hydrolyzes long-chain fatty acids of triacylglycerol.
  • Products: Fatty acids, glycerol, and 2-monoacylglycerol.
• Cholesterol Esterase:
  • Site of action: Small intestine
  • Hydrolyzes cholesterol esters
  • Products: Fatty acids and cholesterol
• Phospholipase A2:
  • Secreted by the pancreas and found in the small intestine
  • Hydrolyzes phospholipids at the sn-2 position.
  • Products: Free fatty acid and lysophospholipid.
• Lipoprotein Lipase (LPL):
  • Present on the capillary walls of adipose tissue and muscles.
  • Hydrolyzes triacylglycerol in VLDL and chylomicrons.
  • Products: Free fatty acids and glycerol.
• Hormone-Sensitive Lipase (HSL):
  • Site of action: Adipose tissue.
  • Important during fasting and starvation, involved in lipolysis.
  • Hydrolyzes triacylglycerol into fatty acids and glycerol.
• Hepatic Lipase:
  • Site of action: Liver
  • Involved in remodeling lipoproteins.
  • Products: Free fatty acids and diacylglycerol/monoacylglycerol.