Lipid Metabolism Notes

Lipid Metabolism

Lipid Digestion and Absorption

• Functions of Fatty Acids:

  • Fuel molecules stored as triglycerides.

  • Components of phospholipids and glycolipids.

  • Attachment to proteins for membrane targeting.

  • Hormones and intracellular messengers.

• Triglycerides (TAGs):

  • 98% of ingested lipids.

  • Stored in adipose tissue as TAGs with ester linkages to glycerol.

  • Stored in adipocytes within large droplets.

  • Adipose tissue is prominent in subcutaneous and visceral deposits.

• Digestion in the Stomach:

  • Gastric lipase hydrolyzes ~10% of TAGs.

  • Produces fats, diacylglycerols, short-chain and medium-chain fatty acids, phospholipids, and cholesterol esters.

• Digestion in the Duodenum:

  • Lipids are emulsified by bile salts (synthesized from cholesterol in the liver).

  • Bile salts are amphipathic molecules that insert into lipid droplets, aiding digestion.

• Bile Salts:

  • Derived from cholesterol with added polar groups.

  • Break up fat globules into smaller, hydrophilic droplets.

• Digestion and Absorption in the Small Intestine:

  • Emulsified fats (TAGs) are hydrolyzed by pancreatic lipase into two fatty acids and monoacylglycerol (MAG).

  • Free fatty acids and MAG are carried in micelles to the intestinal epithelium for absorption.

  • Micelles are formed by small lipids in aqueous solutions, with polar heads facing outward and non-polar tails sequestered inward.

Micelle Formation and Lipid Absorption

• Micelle Formation:

  • Facilitated by bile salts on the exterior.

  • Mixed micelles contain fatty acids, diacylglycerols (DAG), monoacylglycerols (MAG), phospholipids, cholesterol, vitamins A, D, E, K, and bile salts.

  • Free fatty acids and MAG are absorbed by intestinal epithelial cells via diffusion.

• Chylomicron formation:

  • In intestinal cells, triglycerides are reformed from fatty acids and monoacylglycerol, then packaged into chylomicrons.

  • Chylomicrons are released into the lymph system and then into the bloodstream.

  • Triglycerides are stored in adipose tissue and muscle and can be oxidized in muscle for energy.

Lipid Transport - Lipoproteins

• Lipoproteins:

  • Transport phospholipids, triglycerides, cholesterol, and cholesterol esters.

  • Composed of protein(s) and various lipids.

  • Proteins solubilize lipids and direct particles to specific targets.

  • Classified by density (more lipid = less dense).

• Types of Lipoproteins:

  • Chylomicrons transport exogenous lipids from the intestine.

  • VLDL, IDL, LDL, and HDL transport endogenous lipids between tissues.

• Basic Lipoprotein Structure:

  • Non-polar lipid core: triacylglycerols (TAG) and cholesterol esters (CE).

  • Polar outer coat: phospholipids (PL), free cholesterol (C), and apolipoproteins (P).

• Exogenous pathway

  • Lipoprotein lipase (LPL) breaks down triacylglycerols in chylomicrons and release fatty acids and MAG into tissue fluid

• Endogenous Pathway:

  • Cholesterol and TAG are made in the liver and transported in lipoproteins to other tissues.

  • LDL delivers cholesterol from the liver to peripheral tissues via receptor-mediated endocytosis.

  • HDL carries cholesterol from blood back to the liver (reverse cholesterol transport).

  • HDL is considered “good” cholesterol as it removes excess cholesterol from blood vessels.

Lipolysis

• Lipolysis:

  • Catabolic process breaking down triacylglycerols (TAGs) into fatty acids and glycerol.

  • Occurs in the cytosol of adipose cells.

  • Hormone-sensitive lipase hydrolyzes triacylglycerol at C1 and C3 positions to form monoacylglycerol (MAG).

  • Epinephrine and glucagon activate PKA, which activates hormone-sensitive lipase.

  • Insulin has the opposite effect.

• Lipoprotein Lipase vs. Hormone-Sensitive Lipase:

  • Lipoprotein lipase is extracellular, while hormone-sensitive lipase is intracellular.

• Transport of Fatty Acids:

  • Released fatty acids are bound by serum albumin for transport in the bloodstream.

Fatty Acid Degradation

• Step 1: Synthesis of Acyl CoA:

  • Fatty acid (FA) is activated by forming a thioester link with CoA, catalyzed by fatty acyl CoA synthetase in the outer mitochondrial membrane.
    $Fatty\ acid + CoA + ATP \rightarrow acyl\ CoA + AMP + PPi$
    $PPi \rightarrow 2Pi$

  • Activation consumes 2 ATPs.

  • Acyl CoA is transported into the mitochondria via the carnitine shuttle.

• Step 2: Transport of Acyl CoA (Carnitine Shuttle):

  • The inner mitochondrial membrane is impermeable to long-chain acyl CoA.

  • Acyl group is transferred from CoA to carnitine by carnitine acyltransferase I (CAT I).

  • Acyl-carnitine is transported across the inner membrane by a translocase, transformed back to acyl-CoA by carnitine acyltransferase II (CAT II).

• Step 3: Fatty Acid Oxidation ($\beta$-oxidation):

  • Main pathway to generate energy.

  • FAs are converted into acyl-CoA derivatives in the mitochondrial matrix.

  • Metabolized by sequential removal of 2-carbon acetyl CoA units from the carboxyl end of the acyl-chain.

  • Occurs mainly in the liver and muscle.

  • Each cycle involves 4 reaction steps and is regulated by hormonal and allosteric controls.

$\beta$-Oxidation

• Process:

  1. $\beta$-oxidation: Fatty acids undergo oxidative removal of successive two-carbon units in the form of acetyl-CoA.

  2. Acetyl-CoA is oxidized to carbon dioxide in the citric acid cycle within the mitochondrial matrix.

  3. Electrons produced from oxidative processes (NADH, FADH2) enter the mitochondrial electron transport chain (ETC) to produce ATP.

• Coenzyme A (CoA-SH):

  • Thiol group is the point of attachment to the acyl group, forming a thioester linkage.

• Energy Yield (Palmitate Example): $Palmitate + ATP + CoA \rightarrow Palmitoyl-CoA + AMP + PPi - 2 ATP$ $Palmitoyl-CoA + 7CoA + 7FAD + 7NAD^+ + 7H<em>2O \rightarrow 8Acetyl-CoA + 7FADH</em>2 + 7NADH + 7H^+$ $7FADH_2 \rightarrow 7 \times 1.5 ATP = +10.5 ATP$ $7NADH \rightarrow 7 \times 2.5 ATP = +17.5 ATP$ $8Acetyl-CoA \rightarrow TCA \rightarrow 8 \times 10 ATP = +80 ATP$

  • Net ATP yield for palmitate (C16): 108 - 2 = 106 ATP.

Lipogenesis

• I. Synthesis of Fatty Acids: De Novo Lipogenesis (DNL):

  • De novo pathway: synthesis of complex molecules from simple molecules.

  • Fatty acids can be synthesized from carbohydrates via acetyl CoA under energy excess conditions.

  • Occurs in tissues like liver, adipose tissue, brain, lung, mammary gland (cytosolic).

  • Requires NADPH, ATP, biotin, and bicarbonate (as a CO2 source).

  • Palmitate (16:0) is the end product.

• II. Key Differences Between Lipogenesis and $\beta$-Oxidation:
  

  Feature	Lipogenesis (Synthesis of Fatty Acids)	Lipolysis ($\beta$-Oxidation)
  Location	Cytosol	Mitochondria
  Process	Addition of 2C units from malonyl CoA	Sequential removal of 2C units
  Reducing Agent	NADPH	NADH are produced
  Acyl Carrier	ACP (Acyl Carrier Protein)	CoA
  Enzyme System	Fatty Acid Synthase (single complex)	Many individual enzymes
  III. Synthesis of Fatty Acids: Step 1 Citric Acid Shuttle:

  • FAs are synthesized in the cytosol, but acetyl CoA is produced in the mitochondria.

  • Acetyl CoA combines with oxaloacetate (OAA) to form citrate.

  • Citrate is transported into the cytosol and cleaved to regenerate acetyl CoA and oxaloacetate by ATP-citrate lyase (ATP-dependent).

  • OAA returns to the mitochondrial matrix through conversion to malate by MDH, then pyruvate by NADP+-linked malic enzyme, generating NADPH for FA synthesis.

  • Pyruvate is carboxylated to form OAA in the matrix of mitochondria.

• IV. Synthesis of Fatty Acids: Step 2 Formation of Malonyl CoA:

  • Irreversible, rate-limiting step: carboxylation of acetyl CoA (2C) to form malonyl CoA (3C) by acetyl CoA carboxylase with biotin as a prosthetic group.
    $Acetyl\ CoA + CO_2 + ATP \rightarrow Malonyl\ CoA + ADP + Pi$

  • One molecule of ATP is hydrolyzed.

  • Similar to synthesis of all biopolymers, fatty acid synthesis requires an activation step.

• V. Synthesis of Fatty Acids: (3) Formation of Saturated Long-Chain Fatty Acids:

  • Fatty acid synthase catalyzes the synthesis of saturated long-chain fatty acids from acetyl CoA, malonyl CoA, and NADPH.

• Reaction for the synthesis of palmitate:
  $Acetyl-CoA + 7Malonyl-CoA + 14NADPH + 6H^+ \rightarrow Palmitate + 7CO<em>2 + 14NADP^+ + 8CoA + 6H</em>2O$

Regulation of Fatty Acid Synthesis

• Main Control: Acetyl CoA carboxylase (ACC) reaction (synthesis of malonyl CoA).

• ACC is switched off by phosphorylation (by AMP-dependent protein kinase, AMPK) and activated by dephosphorylation (by protein phosphatase 2A).

• Hormonal Regulation:

  1. When energy is required, glucagon and epinephrine inhibit protein phosphatase 2A, ACC remains off.

  2. When blood glucose levels are high, insulin will turn on ACC.

• When energy charge is low with a high AMP content, AMP-dependent protein kinase is activated, inhibiting malonyl CoA production.

Ketone Bodies

• Ketone Bodies: Acetone, acetoacetate and $\beta$-hydroxybutyrate

• Synthesis occurs in mitochondria of liver cells (hepatocytes).

• Can be used as fuel by the brain and other tissues such as heart muscle during starvation (after 2-3 days, body shifts fuel use from glucose to FA and ketone bodies).

• Water-soluble and exported into the blood to other tissues.

• Converted into acetyl CoA for processing by the TCA cycle.

• Liver, lacking the converting enzyme e.g. CoA transferase ∴ketone bodies after produced are not metabolized in liver, but transporting them out to other tissues