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CHAPTER 21 Lipid Biosynthesis (Week 4) - Coggle Diagram
CHAPTER 21
Lipid Biosynthesis
(Week 4)
Regulation of Cholesterol Synthesis and Transport
Longer-Term Regulation of HMG-CoA Reductase
Through Transcriptional Control
Sterol regulatory element-binding proteins(SREBPs)
When sterol levels are high, SREBPs are in the ER membrane with other proteins.
When sterol levels decline, the complex is cleaved and moves to the nucleus.
It activates transcription of HMG-CoA reductase and LDL receptor, as well as other genes.
Regulation of Cholesterol Synthesis by SREBP
Regulation of Cholesterol Metabolism
Regulation of HMG-CoA Reductase by Proteolytic Degradation
HMG-CoA Reductase Is Most
Active When Dephosphorylated
AMP-dependent protein kinase – when AMP rises, kinase phosphorylates the enzyme => activity up, cholesterol synthesis down
Glucagon, epinephrine – cascades lead to phosphorylation, down activity
Insulin – cascades lead to dephosphorylation,up activity
Covalent modification provides short-term regulation.
Regulation by LXR-Mediated Transcription
Five Modes of Regulation of Cholesterol
Synthesis and Transport
Covalent modification of HMG-CoA reductase
Transcriptional regulation of HMG-CoA gene
Proteolytic degradation of HMG-CoA reductase
Activation of ACAT, which increases esterification for storage
Transcriptional regulation of the LDL receptor
The Genes Activated by LXR-RXR Are Largely for Cholesterol Transport
Acetyl-CoA carboxylase – first enzyme in fatty acid synthesis
Apolipoproteins (C1, C2, D, and E) – for cholesterol transport
GLUT4
ABC transporters – for reverse cholesterol transport
Regulate
ACC Is Also Regulated by Covalent Modification
Inhibited when energy is needed
Glucagon and epinephrine:
– reduce sensitivity of citrate activation
– lead to phosphorylation and inactivation of ACC
ACC is active as dephosphorylated monomers.
When dephosphorylated, ACC polymerizes into long inactive filaments.
Phosphorylation reverses the polymerization.
Regulation of Fatty Acid Synthesis in Vertebrates
Fatty Acid Synthesis Is Tightly Regulated via ACC
Acetyl CoA carboxylase (ACC) catalyzes the rate-limiting step.
ACC is feedback-inhibited by palmitoyl-CoA.
ACC is activated by citrate.
• Citrate is made from acetyl-CoA in mitochondria (acetyl-CoAmt). • Citrate signals excess energy to be converted to fat.
When [acetyl-CoA]mt up is converted to citrate… citrate is exported to cytosol.
Additional Modes of Regulation in Fatty Acid Synthesis
Changes in gene expression– example:
Fatty acids (and eicosanoids) bind to transcription factors called peroxisome proliferator-activated receptors (PPARS).
Reciprocal regulation
– Malonyl-CoA inhibits fatty acid import into mitochondria.
one of many ways to ensure that fat synthesis and oxidation don’t occur simultaneously
Stearate to Desaturated
Eicosanoids Are Potent Short-Range
Hormones Made from Arachidonate
Eicosanoid hormones include prostaglandins, leukotrienes, thromboxanes.
Created from the arachidonate that is incorporated into the phospholipids of membranes.
In response to stimuli (hormone, etc.), phospholipase A 2 is activated and attacks the C-2 fatty acid, releasing arachidonate.
Conversion of Arachidonate to Prostaglandins and Other Eicosanoids
Plant Desaturases Act on
Fatty Acids on a Phospholipid
Unlike mammal desaturases, plant desaturases do not oxidize free fatty acids.
They oxidize fatty acids that are bound to glycerol in phosphatidylcholine.
Free desaturated fatty acids can then be hydrolyzed from the glycerol backbone.
PGH 2 Synthase Has Two Isoforms
COX-1 catalyzes synthesis of prostaglandins that regulate gastric mucin secretion.
COX-2 catalyzes synthesis of prostaglandins that mediate pain, inflammation, and fever.– NSAIDs (aspirin, ibuprofen, acetaminophen) inhibit COX-2.
Plants Can Desaturate Positions Beyond C-9
Humans have Δ4, Δ5, Δ6, and Δ9 desaturases but cannot desaturate beyond Δ9.
Plants can produce: linoleate 18:2(Δ9,12) 、α-linolenate 18:3 (Δ9,12,15)
These fatty acids are “essential” to humans.
-Polyunsaturated fatty acids (PUFAs) help control membrane fluidity.
-PUFAs are precursors to eicosanoids.
NSAIDs Inhibit Cyclooxygenase (COX) Activity
Desaturation of a Fatty Acid by
Fatty Acyl-CoA Desaturase
O2 accepts four electrons from two substrates.
Two electrons come from saturated fatty acid.
Two electrons come from ferrous state of cytochrome b5.
Synthesis of Leukotrienes Also Begins with Arachidonate
Palmitate and Stearate Can Be Desaturated
Palmitate(16:0) => palmitoleate(16:1; Δ9)
Stearate (18:0) => oleate (18;1; Δ9)– catalyzed by fatty acyl-CoA desaturase inanimals
also known as the fatty acid desaturases
requires NADPH; enzyme uses cytochrome b5 and cytochrome b5 reductase
Note that this is a Δ9-desaturase!It reduces the bond between C-9 and C-10.
Statin Drugs Inhibit HMG-CoA Reductase to Lower Cholesterol Synthesis
Statins resemble mevalonate => competitive inhibitors of HMG-CoA reductase
First statin, lovastatin, found in fungi – lowers serum cholesterol by tens of percent
Also reported to improve circulation, stabilize plaques by removing cholesterol from them, and reduce vascular inflammation
Reverse Cholesterol Transport by HDL Explains Why HDL Is Cardioprotective
Familial Hypercholesterolemia
Due to genetic mutation in LDL receptor • Impairs receptor-mediated uptake of cholesterol
from LDL • Cholesterol accumulates in the blood and in foam
cells. • Regulation mechanisms based on cholesterol
sensing inside the cell don’t work. • Homozygous individuals can experience severe
CVD as youths.
There Are Several Classes of
Cholesterol-Derived Steroids
Adrenal gland-synthesized steroids:
mineralcorticoids
glucocorticoids
Gonad-synthesized steroids:
progesterone, androgens, estrogems
How Plaques Form
Steroid Hormones Derived from Cholesterol
Cardiovascular Disease (CVD) Is Multifactorial
Very high LDL-cholesterol levels tend to correlate with atherosclerosis.
Low HDL-cholesterol levels are negatively associated with heart disease.
Side-Chain Cleavage in Steroid Synthesis
膽固醇合成
Glyceroneogenesis Makes DHAP for Glycerol 3-Phosphate Generation During TAG Cycle
During lipolysis (stimulated by glucagon or epinephrine), glycolysis is inhibited.– So DHAP is not readily available to make glycerol 3-phosphate.– And adipose cells don’t have glycerol kinase to make glycerol 3-phosphate on site.
Glyceroneogenesis contains some of the same steps of gluconeogenesis.– converts pyruvate => DHAP – basically, an abbreviated version of gluconeogenesis in the liver and adipose tissue
Glyceroneogenesis
What Is the Source of the Glycerol 3-Phosphate
Needed for Fatty Acid Reesterification?
During lipolysis (stimulated by glucagon or epinephrine), glycolysis is inhibited.
– So DHAP is not readily available to make glycerol 3-phosphate.
And adipose cells don’t have glycerol kinase to make glycerol 3-phosphate on site.
So cells make DHAP via glyceroneogenesis.
See next slide.
Biosynthesis of Membrane Phospholipds
Regulation of Triacylglycerol Synthesis by Insulin
Attaching Phospholipid Head Group
Requires Activation by CDP
The Triacylglycerol Cycle
Phosphatidic Acid Can Be Modified to Form Phosphlipids or TAGs
Triacylglycerol Breakdown and
Resynthesis create a Futile Cycle
Seventy-five percent of free fatty acids (FFAs) released by lipolysis are reesterified to form TAGs, rather than be used for fuel.
– Some recycling occurs in adipose tissue.
– Some FFAs from adipose cells are transported to the liver, remade into TAG, and redeposited in adipose cells.
• Although the distribution between these two paths may vary, overall, the percentage of FFAs being esterified remains at ~75%.
Phospholipid Synthesis in E. coli
Synthesis of Phosphophatidic Acid Occurs Before TAGs
Fat (Triacylglycerol) and Phospholipids in Animals, Plants, and Bacteria
Animals and plants store fat for fuel.
– plants: in seeds, nuts
– typical 70-kg human has ~15 kg fat
enough to last 12 weeks
compare with 12 hours worth of glycogen in liver and muscle
Animals and plants and bacteria make phospholipids for cell membranes. • Both molecules contain glycerol backbone and 2 (e.g.,phospholipids) or 3 (e.g.,triacylglycerides) fatty acids.
Synthesis of Phosphatidylserine and Phosphatidylcholine in Mammals Constitutes a Salvage Pathway
Synthesis of Backbone of TAGs and Phospholipids
Summary of Phospholipid Biosynthesis Pathways in Eukaryotes
Synthesis and Transport of Cholesterol
Steps
Conversion of Squalene to Cholesterol
Overview of Eukaryotic Cholesterol Biosynthesis
Fates of Cholesterol After Synthesis
In vertebrates, most cholesterol is
synthesized in the liver, then exported
.
They are exported as bile acids, biliary cholesterol, or cholesteryl esters.
Bile is stored in the gall bladder and secreted into the small intestine after fatty meal.
Bile acids such as taurocholic acid emulsify fats.
They surround droplets of fat, increasing surface area for attack by lipases.
Other tissues convert cholesterol into steroid
hormones and so on.
Synthesis and Transport of Cholesterol, Steroids, and Isoprenes
Compounds are chemically related and distinct from TAGs, phospholipids, sphingolipids, and plasmalogens.
Chemical relationship is built on biosynthesis using 5-carbon isoprene unit
Cholesterol and Other Lipids Are
Carried on Lipoprotein Particles
Lipids are carried through the plasma on spherical particles.
surface is made of protein (called apolipoprotein) and a phospholipid monolayer
interior contains cholesterol, TAGs, and cholesteryl esters, which are more nonpolar than cholesterol
Four Major Classes of Lipoprotein Particles
Named based on position of sedimentation (density) in centrifuge
Composition varies between class of lipoprotein
Includes four major classes:
Apolipoproteins in Lipoproteins
Lipoproteins
VLDL
LDL
Chylomicrons
HDL
Lecithin-Cholesterol Acyl Transferase- Catalyzed Reaction Occurs in HDL
Biological Roles of Lipoproteins in Trafficking Cholesterol and TAGs
Cholesterol Uptake by Receptor- Mediated Endocytosis
Elongation
Elongation systems in the endoplasmic reticulum and mitochondria create longer fatty acids.
As in palmitate synthesis, each step adds units of 2 C.
Stearate (18:0) is the most common product.