14.4 Lipolysis and Lipid Biosynthesis: Fatty Acids, Triacylglycerols, and Cholesterol

14.4 Lipolysis and Lipid Biosynthesis: Fatty Acids, Triacylglycerols, and Cholesterol

Quick Answer: Lipid metabolism (area G2, 12 items) lists lipolysis, beta-oxidation, ketone bodies, fatty acid synthesis, triacylglycerol synthesis, and cholesterol synthesis. Section 14.2 covers beta-oxidation and ketone bodies. This section covers the breakdown of stored fat and the three biosynthetic pathways, with their key regulatory enzymes, stoichiometry, and drug targets.

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Lipolysis: Mobilizing Stored Fat

Triacylglycerols in adipocytes are hydrolysed in three steps by adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase.

• Fasting and stress hormones (glucagon, adrenaline) activate adenylyl cyclase. cAMP then activates protein kinase A, which phosphorylates HSL and perilipin on the lipid droplet, releasing fatty acids.
• Insulin activates phosphodiesterase, lowering cAMP and stopping lipolysis.
• Free fatty acids travel in blood bound to albumin and are oxidized in muscle, heart, and liver.
• Glycerol goes to the liver, where glycerol kinase phosphorylates it; it is then oxidized to dihydroxyacetone phosphate and enters gluconeogenesis or glycolysis. Adipocytes have little glycerol kinase, so they cannot reuse it.

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Fatty Acid Synthesis

Exporting Acetyl-CoA: The Citrate Shuttle

Acetyl-CoA is made in mitochondria, but fatty acid synthesis runs in the cytosol. Citrate carries the acetyl group out:

1. Citrate synthase forms citrate in the matrix, and the citrate is exported.
2. ATP-citrate lyase in the cytosol splits citrate into acetyl-CoA and oxaloacetate, using ATP.
3. Oxaloacetate is reduced to malate, and malic enzyme decarboxylates malate to pyruvate, producing NADPH.

The Committed Step: Acetyl-CoA Carboxylase (ACC)

$\text{acetyl-CoA} + HCO_3^- + ATP \xrightarrow{\text{biotin}} \text{malonyl-CoA} + ADP + P_i$

Malonyl-CoA also inhibits carnitine palmitoyltransferase I, so newly made fatty acids are not sent straight into beta-oxidation.

The Fatty Acid Synthase Cycle

Mammalian fatty acid synthase is a large multifunctional dimer. The growing chain is attached to the phosphopantetheine arm of the acyl carrier protein (ACP). Each turn adds two carbons:

1. Condensation (ketoacyl synthase): the acyl group condenses with malonyl-ACP, releasing $CO_2$. The decarboxylation drives the reaction.
2. Reduction (ketoacyl reductase) with NADPH gives a D-3-hydroxyacyl group.
3. Dehydration (dehydratase) gives a trans-enoyl group.
4. Reduction (enoyl reductase) with NADPH gives a saturated acyl group.

After seven cycles, thioesterase releases palmitate (C16).

$8\ \text{acetyl-CoA} + 7\ ATP + 14\ NADPH + 14\ H^+ \rightarrow \text{palmitate} + 8\ CoA + 7\ ADP + 7\ P_i + 14\ NADP^+ + 6\ H_2O$

The 7 ATP are spent by ACC making 7 malonyl-CoA. NADPH comes from the pentose phosphate pathway and malic enzyme.

Synthesis Compared with Beta-Oxidation

Elongation and Desaturation

Enzymes on the endoplasmic reticulum lengthen palmitate using malonyl-CoA, giving stearate (C18) and longer chains. Desaturases introduce cis double bonds: the delta-9 desaturase converts stearate to oleate. Humans cannot add double bonds beyond carbon 9, so linoleic acid (omega-6) and alpha-linolenic acid (omega-3) are essential. They are precursors of arachidonic acid, eicosanoids, EPA, and DHA.

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Triacylglycerol and Phospholipid Synthesis

1. Glycerol-3-phosphate comes from dihydroxyacetone phosphate (glycerol-3-phosphate dehydrogenase) or, in liver, from glycerol (glycerol kinase).
2. Two acyl-CoAs acylate it, giving phosphatidic acid.
3. A phosphatase removes the phosphate, giving diacylglycerol.
4. A third acyl-CoA gives triacylglycerol.

Phosphatidic acid and diacylglycerol are branch points for phospholipids: CDP-diacylglycerol leads to phosphatidylinositol, and CDP-choline plus diacylglycerol gives phosphatidylcholine.

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Cholesterol Synthesis

All 27 carbons of cholesterol come from acetyl-CoA, 18 acetyl-CoA molecules in total.

Regulation of HMG-CoA reductase:

• Sterol feedback through SREBP: low cellular cholesterol releases this transcription factor, which raises HMG-CoA reductase and LDL-receptor expression. High sterol levels also speed degradation of the enzyme.
• Hormones and energy: insulin promotes the active dephosphorylated form, while glucagon and AMPK phosphorylation inactivate it.
• Statins are competitive inhibitors that lower blood LDL cholesterol.

Cholesterol is the precursor of bile acids, steroid hormones (cortisol, aldosterone, sex hormones), and vitamin D.

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Lipoproteins