BMB 3110 Lecture 29: Lipid Synthesis

Overview

• Storage and Membrane Lipids
• Cholesterol Synthesis
• Cholesterol Regulation and Transport

Notable Quote:
"Perfumes, colors, and sounds echo one another."
--Charles Baudelaire, quoted in Biochemistry, 4th Ed.

Learning Goals

At the end of this lecture, you should:

• Understand the main classes of membrane lipids
• Know the precursors of phospholipids and sterols, as well as their sources
• Be familiar with the regulated steps in lipid synthesis
• Understand how intermediates in lipid synthesis interconnect with other pathways
• Predict the leaflet where a lipid will be found based on its head group identity
• Know the major lipid carriers in the blood

Lipid Pathways in Context

• Key Metabolites and Pathways:

  • Glucose
  • DHAP (Dihydroxyacetone phosphate)
  • Glycerol 3-phosphate (Important for lipid synthesis)
  • Phosphatidate (A key precursor)

• Active Pathways:

  1. Glycolysis (Refer to Chapter 16)
  2. Triacylglycerol breakdown (Refer to Chapter 27)
  3. Triacylglycerol synthesis (Chapter 29)
  4. Phospholipid synthesis (Chapter 29)

• Tissues Involved:

  • Liver
  • Adipose Tissue (Diet may influence these pathways)

Phosphatidate

• Definition:
  • Phosphatidate (diacylglycerol 3-phosphate) acts as a backbone for many lipids.
• Formation:
  • Formed through the addition of two fatty acids to glycerol 3-phosphate.

Making Triacylglycerol

• Function of Phosphatidate:
  • Phosphatidate serves as a scaffold in both:
  • Storage lipids
  • Phospholipids
• Synthesis Process:
  • For storage lipids, a third fatty acid is added to phosphatidate, forming triacylglycerol.
  • This process is catalyzed by the triacylglycerol synthetase complex, bound to the endoplasmic reticulum (ER) membrane.
  • Primary location: Liver Tissue
  • Triacylglycerol can then be:
    • Transferred to muscle for fuel.
    • Stored in adipose tissue.
• Insight:
  • Triglycerides constitute the primary storage form of energy in humans, amounting to 85%.

Phospholipids

• Definition:
  • Phospholipids (also termed phosphoglycerides) are crucial components of cell membranes.
• Components:
  • A phospholipid is made up of:
  • A backbone (either glycerol or sphingosine)
  • Two fatty acids
  • A phosphorylated alcohol
• Additional Roles:
  • Besides membranes, phospholipids are also found in:
  • Lung surfactants.
  • Some signaling molecules.

Glycerophospholipids

• Definition:
  • Glycerophospholipids (which utilize a glycerol backbone) are a combination of DAG (diacylglycerol) and alcohol.
• Activation:
  • One component needs to be converted into an activated precursor.
  • Activation example:
  • For DAG, CDP-diacylglycerol is formed when CTP reacts with phosphatidate.
  • The reaction is driven by the hydrolysis of PPi (pyrophosphate).
• Reaction:
  • CDP-diacylglycerol then reacts with the -OH group in an alcohol. Products yield:
  • Phospholipid
  • CMP (cytidine monophosphate).

Activation of Glycerophospholipids

• Specific Reactions:
  • The resulting product from CDP-diacylglycerol depends on the alcohol that it reacts with:
  • Inositol: produces phosphatidylinositol. Additional phosphorylations yield PIP2.
  • Phosphatidylglycerol: leads to cardiolipin
  • Typically situated in the inner leaflet (involved in signaling).
• For other glycerophospholipids:
  • The alcohol (instead of DAG) is activated, e.g.,
  • Phosphatidylethanolamine:
    • CDP-alcohol releases CMP upon reaction with diacylglycerol.
  • Phosphatidylcholine:
    • A pivotal component in mammalian membranes (~50%).
    • Formed via CDP-choline, with the potential for synthesis from phosphatidylethanolamine.

Regulation of Lipid Synthesis

• Key Regulatory Factors:
  • The relative amounts of diacylglycerol and phosphatidate dictate lipid synthesis levels.
  • Phosphatidic acid phosphatase increases diacylglycerol levels.
  • Diacylglycerol kinase increases phosphatidate levels.
  • Implications of Activity:
  • Loss of phosphatase activity can lead to reduced body fat and insulin resistance in mice.

Sphingolipids

• Definition:
  • Sphingolipids are membrane lipids present in all eukaryotic cells.
• Structure:
  • Unlike glycerophospholipids, sphingolipids possess a sphingosine backbone.
• Sphingosine Precursors:
  • Derived from palmitate and serine.
• First Sphingolipid:
  • Ceramide is formed by adding fatty acid to sphingosine.
  • Other sphingolipids arise from modifications at the terminal hydroxyl group of ceramide.

Pathway to Ceramide

• Illustration
  • Ceramide formation pathway involves various biochemical transformations, illustrating how sphingolipids are synthesized from palmitoyl and serine through intermediates like 3-ketosphinganine, dihydro-sphingosine, and dihydroceramide.

Sphingolipids: Head Groups

• Varieties:
  • Different sphingolipids are created by attaching activated precursors to ceramide:
  • Sphingomyelin:
    • Important in the myelin sheath, features a phosphorylcholine head group.
  • Cerebroside:
    • Contains glucose or galactose as the head group.
  • Ganglioside:
    • Contains additional sugars and is integral in immune system binding sites.

Functions of Sphingolipid Head Groups

• Roles:
  • ABO blood group determination (via sugars).
  • Bacterial and viral binding sites (e.g., via gangliosides).
• Clinical Aspects:
  • Defects in degradation can lead to diseases, such as Tay-Sachs disease.

Cholesterol

• Significance:
  • Cholesterol is a critical lipid component in animal cells, essential for maintaining membrane fluidity and as a precursor for steroid hormones (e.g., testosterone, estradiol).
• Synthesis Site:
  • The liver is the primary site for cholesterol synthesis.
• Synthesis Breakdown:
  • Divided into three stages:
  1. Production of activated five-carbon isoprene precursors (in cytoplasm).
  2. Condensation of six isopentenyl pyrophosphates to form squalene (30 carbons).
  3. Cyclization of squalene to yield the 27-carbon cholesterol molecule.

Cholesterol Synthesis: Initial Steps

• First Step:
  • Formation of HMG-CoA from acetyl CoA and acetoacetyl CoA originating from the same source.
• Committed Step:
  • Catalyzed by HMG-CoA reductase, which is crucial for regulating cholesterol synthesis.

Cholesterol: Further Steps

• Five-carbon precursors:
  • Isopentenyl pyrophosphate is derived from mevalonate (activated isoprene unit).
• Squalene Assembly:
  • Occurs in the lumen of the endoplasmic reticulum, formed from five-carbon precursors (six total), following the sequence $C<em>5 o C</em>{10} o C<em>{15} o C</em>{30}$.

Cholesterol: Cyclization and Formation

• Squalene Cyclization:
  • Results in the formation of lanosterol (a tetracyclic structure).
  • Subsequent steps remove three carbons, leading to the formation of cholesterol.

Cholesterol Regulation of Synthesis

• Feedback Inhibition:
  • Cholesterol production adapts to existing cholesterol levels, with regulation primarily via HMG-CoA reductase activity.
• Mechanisms of Regulation:
  1. Transcriptional Control
  2. Translational Control
  3. Protein Stability Control
  4. Phosphorylation State Control
  • Each mechanism can yield up to a 200-fold difference in enzyme abundance.

Cholesterol Regulation: Transcriptional Control

• SREBP (Sterol Regulatory Element Binding Protein):
  • Enhances transcription of the HMG-CoA reductase gene upon binding to DNA.
  • In its inactive form, SREBP resides in the ER membrane with SCAP (SREBP cleavage-activating protein).
  • SREBP is activated when cellular cholesterol levels are low, directing it to the Golgi for proteolytic cleavage.
  • SCAP's behavior with SREBP is dictated by cholesterol levels in the cell.

Cholesterol Transport through Lipoproteins

• Cholesterol and Triacylglycerols:
  • Packaged into lipoproteins for transportation throughout the body.
• Lipoprotein Composition:
  • Composed of a hydrophobic core surrounded by a shell of proteins and more polar lipids.
• Lipoprotein Density Sorting:
  • VLDLs (Very Low-Density Lipoproteins): Transport excess TAGs and cholesterol from the liver.
  • IDLs (Intermediate-Density Lipoproteins): Result from TAG unloading and can re-enter the liver or convert into LDLs.
  • LDLs (Low-Density Lipoproteins): Major carriers of cholesterol into cells.
  • HDLs (High-Density Lipoproteins): Mediate reverse cholesterol transport from dying cells back to the liver.

LDL: Mechanism of Cell Entry

• Entry Process:
  • LDL access to cells occurs via receptor-mediated endocytosis:
  1. LDL binds to the cell-surface LDL receptor.
  2. The receptor-LDL complex undergoes internalization.
  3. LDL is hydrolyzed within lysosomes while the receptor is recycled to the cell surface.

Clinical Insight: Familial Hypercholesterolemia

• Condition Overview:
  • Familial hypercholesterolemia arises from defective or absent LDL receptors.
• Outcomes:
  • Leads to elevated cholesterol and LDL in plasma.
  • Accumulation can cause nodules (xanthomas) and coronary artery deposition.
  • Oxidized LDL triggers an immune response, resulting in foam cell formation in blood vessels and plaque development.

Clinical Insight: Managing Cholesterol Levels

• Reverse Transport:
  • HDL levels correlate with a reduced risk of atherosclerosis.
  • High HDL is thought to prevent macrophage conversion into foam cells.
• Treatment Goals for Hypercholesterolemia:
  • Strategies to lower blood cholesterol:
  • Bile Salt Reabsorption Prevention: Using negatively charged polymers to bind bile salts and prevent absorption.
  • Competitive HMG-CoA Reductase Inhibitors: e.g., Statins (such as lovastatin).
  • Such treatments can yield approximately a 50% reduction in plasma cholesterol levels.

Cholesterol as a Precursor to Bile Salts

• Function in Digestion:
  • Bile salts act as effective detergents, aiding in the solubilization of dietary lipids.
  • Derived from cholesterol and stored in the gallbladder.

Cholesterol as a Precursor: Hormones and Vitamin D

• Steroid Hormones:
  • Cholesterol is a precursor to various classes of steroid hormones, including:
  • Progestogens
  • Glucocorticoids
  • Mineralocorticoids
  • Androgens
  • Estrogens
• Vitamin D Formation:
  • Also synthesized from cholesterol, crucial for calcium and phosphorus metabolism.

Key Concepts from Lecture 29

• Phosphatidate Formation:
  • What is phosphatidate and how is it formed?
• Components of Glycerophospholipid:
  • What are the parts of a glycerophospholipid?
• Comparison:
  • How do sphingolipids differ from glycerophospholipids?
• Triacylglycerol Function:
  • What is triacylglycerol and its role?
• Sphingosine Origin:
  • From what molecules is sphingosine derived?
• Cell Recognition Leaflet:
  • In which leaflet are head groups for cell recognition usually situated?
• Glycerol-based Phospholipid Head Groups:
  • What various head groups are used?
• Glycerophospholipid Activated Precursors:
  • What are the activated precursors for forming glycerophospholipids?
• Key Sphingolipids:
  • What are ceramides, cerebrosides, gangliosides, and sphingomyelin?
• Cholesterol Synthesis Enzyme:
  • Which enzyme catalyzes the committed step in cholesterol synthesis?
• Cholesterol Synthesis Location:
  • Where does cholesterol synthesis take place (specific tissue and cellular components)?
• Lipoproteins in Lipid Trafficking:
  • How are lipoproteins leveraged in lipid, especially cholesterol transportation?
• Hypercholesterolemia Treatments:
  • What strategies exist to treat excessive cholesterol levels?
• Cholesterol Regulation Mechanisms:
  • In what four ways is cholesterol synthesis regulated by cholesterol levels?