12 - Overview of Lipid Metabolism

TARGET DECK: MED::I::Signaling Pathways in Health and Disease::Metabolic Biochemistry::12 - Overview of Lipid Metabolism

Overview of Lipid Metabolism

Contents

• What are lipids
• Digestion, absorption and transport
• Lipolysis
• Beta-oxidation of fatty acids
• Ketone bodies
• Biosynthesis of fatty acids
• Biosynthesis of lipids
• Biosynthesis of cholesterol
• Plasma lipoproteins

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What Are Lipids?

Broad Definition

Lipids are molecules insoluble in water (hydrophobic) and soluble in organic solvents.

Chemical Definition

More specifically, lipids are molecules containing fatty acids.

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Electronegativity and Bond Polarity

Electronegativity Electronegativity is a measure of the tendency of an atom to attract a bonding pair of electrons.

Bond Type	Electronegativity Difference	Electron Sharing	Character
Non-polar covalent	~0	Equal	Hydrophobic
Polar covalent	Moderate	Unequal	Partially hydrophilic
Ionic	Large	No sharing	Hydrophilic

Hydrophilic Molecules Substances that dissolve readily in water are hydrophilic. They are composed of ions or polar molecules that attract water molecules through electrical charge effects.

Hydrophobic Molecules Substances that contain a preponderance of nonpolar bonds are usually insoluble in water. Hydrocarbons, which contain many C–H bonds, are especially hydrophobic.

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Molecules that are insoluble in water and soluble in organic solvents are called {1:lipids}.

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Hydrophobic molecules contain a preponderance of {1:nonpolar bonds} and are not attracted by water molecules.

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Fatty Acids

Definition

Fatty acids are carboxylic acids consisting of a hydrocarbon chain and a terminal carboxyl group, especially those occurring as esters in fats and oils.

They have:

• A polar carboxyl head $(-COOH)$
• A non-polar aliphatic hydrocarbon chain tail

Key Features

• Mostly have an even number of carbon atoms
• Classified as short-chain, medium-chain, or long-chain
• Can be saturated or unsaturated

Saturated vs. Unsaturated Fatty Acids

Type	Description	Example
Saturated	No double bonds	Palmitate 16:0, Stearate 18:0
Monounsaturated	One cis double bond	Oleate 18:1
Diunsaturated	Two cis double bonds	Linoleate 18:2
Polyunsaturated	Multiple cis double bonds	Arachidonate 20:4

Notation for Double Bond Position

Double bond position is expressed:

• $\Delta$ (delta): numbered from the carboxyl end
• $\omega$ (omega): numbered from the distal methyl end

Example: ${\text{CH}}_3{\text{-CH}}_2{\text{-CH=CH-CH}}_2{\text{-CH}}_2{\text{-CH}}_2\text{-COOH}$ is ${\Delta }^5$-octaenoic acid or $\omega 3$-octaenoic acid

Common Naturally Occurring Fatty Acids

Carbon skeleton	Common name	Systematic name	Melting point (°C)
12:0	Lauric acid	n-Dodecanoic acid	44
14:0	Myristic acid	n-Tetradecanoic acid	53.9
16:0	Palmitic acid	n-Hexadecanoic acid	63.1
18:0	Stearic acid	n-Octadecanoic acid	69.6
20:0	Arachidic acid	n-Eicosanoic acid	76.5
24:0	Lignoceric acid	n-Tetracosanoic acid	86.0
16:1(${\Delta }^9$)	Palmitoleic acid	cis-9-Hexadecenoic acid	−0.5
18:1(${\Delta }^9$)	Oleic acid	cis-9-Octadecenoic acid	13.4
18:2(${\Delta }^{9,12}$)	Linoleic acid	cis,cis-9,12-Octadecadienoic acid	−5
18:3(${\Delta }^{9,12,15}$)	α-Linolenic acid	cis,cis,cis-9,12,15-Octadecatrienoic acid	−11
20:4(${\Delta }^{5,8,11,14}$)	Arachidonic acid	cis,cis,cis,cis-5,8,11,14-Icosatetraenoic acid	−49.5

Solubility Trend

As chain length increases, water solubility decreases dramatically (e.g., lauric acid: 0.063 mg/g H₂O → stearic acid: 0.0034 mg/g H₂O). Unsaturation lowers melting point.

Some Examples — Notation Summary

• Stearic acid → 18:0 octadecanoic
• Oleic acid → 18:1 ${\Delta }^9$-octadecenoic ($\omega 9$)
• Linoleic acid → 18:2 ${\Delta }^{9,12}$-octadecadienoic ($\omega 6,\omega 9$)
• Linolenic acid → 18:3 ${\Delta }^{9,12,15}$-octadecatrienoic ($\omega 3,\omega 6,\omega 9$)

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Oleic acid is an {1:18:1} fatty acid with a double bond at position {2:Δ9} ($\omega${3:9}).

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Linoleic acid (18:2) is an {1:essential} fatty acid because it cannot be synthesized by mammals and has double bonds at positions {2:Δ9 and Δ12}.

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The $\Delta$ numbering of fatty acid double bonds starts from the {1:carboxyl} end, while $\omega$ numbering starts from the {2:distal methyl} end.

Mnemonic — $\omega$ Families

“THREE-SIX-NINE, feel fine” → $\omega 3$ (fish oils, linolenic), $\omega 6$ (linoleic, arachidonic), $\omega 9$ (oleic) — decreasing “health fame” order.

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Free Fatty Acids vs. Lipids

Important

• Body concentration of free fatty acids is low
• The large majority of fatty acids are esterified in the form of lipids (storage or membrane lipids)
• Free fatty acids may be found in blood under fasting conditions
• In cells, fatty acids are immediately transformed into CoA derivatives and either oxidized or used for biosynthesis of lipids

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Free fatty acids in cells are immediately converted to {1:CoA derivatives} and either {2:oxidized} or used for {3:biosynthesis of lipids}.

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Classification of Lipids

Storage Lipids (Neutral)

Triacylglycerols (TAG)

• Glycerol backbone esterified with three fatty acids
• ~80% of lipid droplet mass

OCC(COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCC=CCCCCCCCC

(Representative mixed triacylglycerol: 1-stearoyl-2-linoleoyl-3-palmitoyl glycerol)

Membrane Lipids (Polar)

Glycerophospholipids (General Structure)

$\text{sn-1: saturated FA}|\text{sn-2: unsaturated FA}|\text{sn-3: phosphate–head group}$

Glycerophospholipid	Head group (X)	Formula of X	Net charge (pH 7)
Phosphatidic acid	—	H	−1
Phosphatidylethanolamine	Ethanolamine	$-C{H}_2-C{H}_2-N{H}_3^{+}$	0
Phosphatidylcholine	Choline	$-C{H}_2-C{H}_2-N(C{H}_3{)}_3^{+}$	0
Phosphatidylserine	Serine	$-C{H}_2-CH(N{H}_3^{+})-CO{O}^{-}$	−1
Phosphatidylglycerol	Glycerol	—	−1
Phosphatidylinositol 4,5-bisphosphate	myo-Inositol 4,5-bisphosphate	—	−4
Cardiolipin	Phosphatidylglycerol	—	−2

Sphingolipids (General Structure)

Sphingolipid	Head group (X)
Ceramide	H
Sphingomyelin	Phosphocholine
Glucosylcerebroside	Glucose
Lactosylceramide (globoside)	Di-, tri-, or tetrasaccharide
Ganglioside GM2	Complex oligosaccharide

Glycolipids

Glycolipids include neutral glycolipids (glucosylcerebroside, lactosylceramide/globoside, gangliosides) — all built on a ceramide backbone with mono- or oligosaccharide head groups.

Cholesterol

Cholesterol is a steroid in the body. It serves as a precursor to vitamins and many steroid hormones (testosterone, estrogen, cortisol).

[C@@H]1(CC[C@H]2[C@@H]1CC=C3C[C@@H](O)CC[C@@]23C)[C@H](C)CCCC(C)C

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Storage lipids are {1:triacylglycerols}, while membrane lipids include {2:glycerophospholipids}, {3:sphingolipids}, and {4:glycolipids}.

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Cholesterol is a precursor to {1:steroid hormones} (e.g., testosterone, estrogen, cortisol) and {2:vitamins}.

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Major Lipids in Food

Lipid	Examples
Triglycerides	Fats, oils
Phospholipids	Egg yolk, soy
Cholesterol	Animal products

Fatty Acid Composition of Dietary Fats

Fat	Cholesterol (mg/tbsp)	Saturated	Monounsaturated	Polyunsaturated
Canola oil	0	Low	High	Moderate
Safflower oil	0	Low	Low	Very high
Olive oil	0	Low	Very high	Low
Butter	33	High	Moderate	Low
Coconut oil	0	Very high	Low	Very low
Lard	12	High	Moderate	Low
Beef tallow	14	High	Moderate	Low

Tip

Plant oils (canola, safflower, olive) have zero cholesterol and are generally richer in unsaturated fatty acids. Animal fats (butter, lard, tallow) contain cholesterol and more saturated fatty acids.

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Digestion, Absorption, and Transport of Dietary Lipids

Overview

Digestion and absorption of dietary lipids occur in the small intestine, and the fatty acids released from triacylglycerols are packaged and delivered to muscle and adipose tissues.

Steps

1. Emulsification — Bile salts (detergents) emulsify dietary fats in the small intestine, forming mixed micelles.
2. Hydrolysis — Intestinal lipases degrade triacylglycerols to fatty acids and monoacylglycerols.
3. Absorption — Fatty acids and other products are taken up by intestinal mucosal cells (enterocytes) and re-esterified into triacylglycerols.
4. Packaging — TAGs are incorporated with cholesterol and apolipoproteins into chylomicrons.
5. Transport — Chylomicrons move through the lymphatic system, then the bloodstream to tissues.
6. Delivery — Lipoprotein lipase (activated by ApoC-II) in capillaries converts TAGs to fatty acids and glycerol.
7. Uptake — Fatty acids enter myocytes via a specific fatty acid transporter; they bind serum albumin in transit.
8. Oxidation or re-esterification — Fatty acids are oxidized as fuel or re-esterified.

Bile Salts — Emulsification

Structure

Bile salts are amphipathic molecules (e.g., taurocholic acid) that act as biological detergents, lowering the surface tension of fat droplets and forming mixed micelles for lipase access.

OC1CC2CC(O)CCC2(C)C3CCC4(C)C(CCC4C3(C)CC1)C(C)CCC(=O)NCCS(=O)(=O)O

(Taurocholic acid)

Chylomicron Structure

Chylomicron Composition

• Surface: phospholipid monolayer with head groups facing the aqueous phase
• Core: triacylglycerols and cholesteryl esters (>80% of mass)
• Apolipoproteins on surface: ApoB-48, ApoC-III, ApoC-II
• Diameter: 100–500 nm

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Dietary fat digestion occurs in the {1:small intestine}; bile salts emulsify fats by forming {2:mixed micelles}.

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Lipoprotein lipase is activated by {1:ApoC-II} and converts chylomicron {2:triacylglycerols} to {3:fatty acids and glycerol} in capillaries.

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Chylomicrons travel from the intestine through the {1:lymphatic system} before entering the {2:bloodstream}.

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Lipolysis

Definition

Under fasting conditions, triacylglycerols stored in adipocytes are hydrolyzed by hormone-sensitive lipase (HSL).

Hormonal Regulation of Lipolysis

Hormone	Effect on Lipolysis	Mechanism
Adrenaline (epinephrine)	Activates	↑ cAMP → PKA activation
Glucagon	Activates	↑ cAMP → PKA activation
Insulin	Inhibits	↓ cAMP; activates phosphodiesterase

Signal Transduction Cascade

$\text{Glucagon/Adrenaline}\stackrel{\text{GPCR}}{\to }{G}_s\to \text{Adenylyl cyclase}\to \text{cAMP}\to \text{PKA}$

$\text{PKA}\stackrel{\text{phosphorylates}}{\to }\text{HSL}+\text{Perilipin}\to \text{Lipolysis activated}$

Perilipin

Perilipin normally shields the lipid droplet from HSL. Upon phosphorylation by PKA, perilipin is displaced, granting HSL access to the lipid droplet surface.

Products of Lipolysis

• Free fatty acids (FFA) → transported in blood bound to serum albumin
  • Taken up by tissues (e.g., muscle) → oxidized to $C{O}_2$ → ATP
  • In liver → can produce ketone bodies
• Glycerol → released into plasma
  • Phosphorylated by glycerol kinase → glycerol-3-phosphate
  • Oxidized to dihydroxyacetone phosphate (DHAP) by glycerol-3-phosphate dehydrogenase (requires $NA{D}^{+}$, produces $NADH$)
  • DHAP → glyceraldehyde-3-phosphate (by triose phosphate isomerase) → enters glycolysis or gluconeogenesis

Energy Content

About 95% of the biologically available energy of triacylglycerols resides in the three long-chain fatty acids; only 5% is contributed by the glycerol moiety.

Glycerol Fate (Summary Pathway)

$\text{Glycerol}\stackrel{\text{glycerol kinase, ATP}}{\to }\text{Glycerol-3-phosphate}\stackrel{{\text{G3P dehydrogenase, NAD}}^{+}}{\to }\text{DHAP}\stackrel{\text{TPI}}{\to }\text{G3P}\to \text{Glycolysis}$

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Lipolysis is activated by {1:adrenaline} and {2:glucagon}, and inhibited by {3:insulin}.

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In lipolysis signaling, PKA phosphorylates both {1:hormone-sensitive lipase (HSL)} and {2:perilipin}, granting HSL access to the lipid droplet.

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Glycerol released during lipolysis is mainly used in the liver for {1:gluconeogenesis}, entering glycolysis as {2:glyceraldehyde-3-phosphate} after conversion via {3:DHAP}.

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Approximately {1:95%} of the biologically available energy in a triacylglycerol is in the {2:fatty acid} chains; {3:5%} is in the glycerol moiety.

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Free fatty acids released from adipocytes are transported in blood bound to {1:serum albumin}.

Mnemonic — PKA targets in lipolysis

“HSL + Perilipin = Happy Stored Lipids Peripherally Inhibited” → PKA phosphorylates both to activate lipolysis.

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TLDR - 12 - Overview of Lipid Metabolism

Summary — Overview of Lipid Metabolism

• Lipids are hydrophobic molecules (insoluble in water, soluble in organic solvents); chemically defined as molecules containing fatty acids.
• Fatty acids are carboxylic acids with a polar carboxyl head and a non-polar hydrocarbon tail; mostly even-numbered carbon chains; classified as saturated (no double bonds) or unsaturated (cis double bonds); double bond position given by $\Delta$ (from carboxyl) or $\omega$ (from methyl end).
• Key fatty acids: stearic (18:0), oleic (18:1 ${\Delta }^9$, $\omega 9$), linoleic (18:2 ${\Delta }^{9,12}$, $\omega 6$), linolenic (18:3 ${\Delta }^{9,12,15}$, $\omega 3$), arachidonic (20:4 ${\Delta }^{5,8,11,14}$).
• Lipid classes: Storage lipids = triacylglycerols (neutral); membrane lipids = glycerophospholipids, sphingolipids, glycolipids (polar); cholesterol (steroid, precursor to hormones/vitamins).
• Free fatty acids are at low concentration in cells; most are esterified. In blood under fasting, FFAs are bound to serum albumin.
• Digestion: bile salts emulsify → lipases hydrolyze → enterocytes absorb & reassemble TAGs → packaged into chylomicrons (ApoB-48, ApoC-II, ApoC-III) → lymphatics → blood → lipoprotein lipase (activated by ApoC-II) liberates FFA at capillaries → tissues.
• Lipolysis: fasting triggers glucagon/adrenaline → GPCR → $G_s$ → adenylyl cyclase → cAMP → PKA → phosphorylates HSL and perilipin → HSL accesses lipid droplet → TAGs hydrolyzed to FFA + glycerol. Insulin inhibits.
• FFA fate: oxidized in muscle ($\beta$-oxidation → $C{O}_2$ + ATP); in liver can yield ketone bodies.
• Glycerol fate: glycerol kinase → glycerol-3-phosphate → DHAP → G3P → gluconeogenesis (main liver use) or glycolysis. Glycerol provides only ~5% of TAG energy.