Lecture 20: Synthesis of Fatty Acids and Triacylglycerols

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Familial Dyslipoproteinemia

A group of genetic disorders leading to impaired lipoprotein metabolism, resulting in abnormal (elevated) cholesterol and triglyceride levels, significantly increasing cardiovascular risk.

Chylomicrons

Large lipoproteins formed in intestinal enterocytes to transport dietary triglycerides and cholesterol from the gut via the lymphatic system to peripheral tissues. They acquire ApoC-II (LPL activation) and ApoE (liver remnant uptake) from HDL.

Apolipoprotein E (ApoE)

A critical apolipoprotein ligand for remnant receptors on the liver, mediating the uptake of chylomicron and VLDL remnants. The ApoE2/E2 genotype is linked to impaired remnant clearance and Familial Dysbetalipoproteinemia.

Lipid Panel

A standard blood test measuring total cholesterol, HDL, LDL, and triglycerides to assess cardiovascular disease risk and monitor lipid-modifying therapies.

Hypertriglyceridemia

An abnormally high level of triglycerides in the blood (>150 ext{ mg/dL}). Severe hypertriglyceridemia (>500 ext{ mg/dL}) is a major risk factor for acute pancreatitis, and chronic elevation increases cardiovascular risk.

Lipoprotein Lipase (LPL)

An enzyme primarily on capillary endothelial surfaces (adipose, muscle). Activated by ApoC-II, LPL hydrolyzes triglycerides in chylomicrons and VLDL, releasing free fatty acids for tissue uptake.

Ketoacidosis

A severe metabolic acidosis caused by an overproduction and accumulation of ketone bodies (e.g., in uncontrolled diabetes or prolonged starvation) when fatty acid breakdown is excessive.

Steatosis

The abnormal intracellular accumulation of lipids, typically triglycerides. Hepatic steatosis ('fatty liver') is common in alcoholism, obesity, and insulin resistance (NAFLD).

Non-Alcoholic Fatty Liver Disease (NAFLD)

A spectrum of liver conditions characterized by hepatic steatosis in non-alcoholic individuals, strongly linked to insulin resistance, obesity, and metabolic syndrome. Can progress to NASH, cirrhosis, or cancer.

Acetyl-CoA Carboxylase (ACC)

The rate-limiting enzyme in fatty acid synthesis (cytosol). Catalyzes Acetyl-CoA to Malonyl-CoA (Biotin, ATP). Activated by citrate and insulin; inhibited by palmitoyl-CoA, glucagon/epinephrine (via phosphorylation by AMPK).

Phospholipids

Amphipathic lipids forming the basic structure of all biological membranes (lipid bilayer). Composed of glycerol, two fatty acids, a phosphate group, and a head group. Also key for lung surfactant.

Surfactant

A mixture of lipids (mainly dipalmitoylphosphatidylcholine, DPPC, a phospholipid) and proteins, produced by alveolar type II cells. Reduces alveolar surface tension, preventing collapse at end-expiration (e.g., Respiratory Distress Syndrome).

Triglyceride

The main storage form of fat in the body, composed of a glycerol backbone esterified to three fatty acids. Primary energy reserve; high plasma levels (hypertriglyceridemia) are clinically significant.

Myocardial Infarction

A heart attack; irreversible damage to heart muscle due to prolonged ischemia (lack of blood flow), typically caused by an occlusive coronary artery thrombus on an atherosclerotic plaque.

Xanthomas

Visible deposits of cholesterol and other lipids in the skin or tendons, indicative of chronic hyperlipidemia. Palmar xanthomas are characteristic of dysbetalipoproteinemia.

Fatty Acid Synthesis

An anabolic pathway occurring in the cytosol of liver, adipose tissue, and mammary glands, converting excess glucose-derived Acetyl-CoA into fatty acids (primarily palmitate) for energy storage.

Cholesterol

A crucial waxy sterol found in animal cell membranes, a precursor for steroid hormones (estrogen, testosterone, cortisol), vitamin D, and bile acids. Both diet and de novo synthesis contribute.

Lipids

A diverse class of water-insoluble organic molecules (fats, oils, phospholipids, steroids) essential for energy storage, cell membrane structure, and signaling.

Fatty Acids

Carboxylic acids with long hydrocarbon chains; can be saturated (no double bonds) or unsaturated (one or more double bonds). Key components of triglycerides and phospholipids, and serve as fuel.

Bile Salts

Amphipathic cholesterol derivatives synthesized in the liver and secreted into the small intestine. They emulsify dietary fats and form mixed micelles, essential for efficient lipid digestion and absorption.

Arachidonic Acid

An essential \omega-6 polyunsaturated fatty acid (derived from linoleic acid), crucial as a precursor for eicosanoids (prostaglandins, thromboxanes, leukotrienes), potent mediators of inflammation and other physiological processes.

Malabsorption

Impaired absorption of nutrients by the small intestine, leading to symptoms like steatorrhea, weight loss, and nutritional deficiencies.

Cystic Fibrosis (CF)

An autosomal recessive genetic disorder (CFTR mutation) causing thick, viscous secretions. Leads to pancreatic insufficiency, severely impaired fat digestion (due to lack of pancreatic lipase/colipase), and thus malabsorption.

Abetalipoproteinemia

A rare autosomal recessive disorder (MTP mutation) characterized by the inability to synthesize ApoB-48 and ApoB-100. Results in absent chylomicrons, VLDL, and LDL, leading to severe fat and fat-soluble vitamin malabsorption (steatorrhea, neurological sx, acanthocytes) despite normal digestion.

Disease: ApoE2 homozygosity?

Familial Dysbetalipoproteinemia (Type III Hyperlipoproteinemia). Leads to impaired remnant clearance.

Genotype causing dysbetalipoproteinemia?

ApoE2 homozygosity (E2/E2 genotype).

Role of ApoE?

Ligand for hepatic remnant receptors, mediating uptake of chylomicron and VLDL remnants.

Effect of ApoE2/E2 genotype?

Impaired binding to hepatic remnant receptors, leading to insufficient remnant uptake and their accumulation in plasma.

Which VLDL component is \uparrow in dysbetalipoproteinemia?

VLDL remnants (also known as IDL).

Which chylomicron component is \uparrow in dysbetalipoproteinemia?

Chylomicron remnants.

Skin manifestation of dysbetalipoproteinemia?

Palmar xanthomas (yellowish streaks in palmar creases) and eruptive/tuberous xanthomas.

Xanthomas indicate high levels of what?

Lipids/Cholesterol in the blood.

Enzyme deficiency leading to hypertriglyceridemia?

Lipoprotein Lipase (LPL) deficiency.

Apolipoprotein deficiency leading to hypertriglyceridemia?

ApoC-II deficiency (ApoC-II activates LPL).

Enzyme deficiency causing pancreatitis?

Lipoprotein Lipase (LPL) deficiency, due to severe hypertriglyceridemia.

Apolipoprotein deficiency causing pancreatitis?

ApoC-II deficiency, due to severe hypertriglyceridemia.

Substrate of LPL?

Triglycerides in chylomicrons and VLDL.

What activates LPL?

Apolipoprotein C-II (ApoC-II).

Location of LPL?

Endothelial surface of capillaries (adipose, muscle, heart).

Lipoprotein transporting dietary lipids?

Chylomicrons.

Primary apolipoprotein of chylomicrons?

ApoB-48.

Apolipoprotein acquired by chylomicrons for LPL activation?

ApoC-II (from HDL).

Apolipoprotein acquired by chylomicrons for liver uptake?

ApoE (from HDL).

Lipoprotein transporting endogenous lipids?

VLDL (Very Low-Density Lipoprotein).

Primary apolipoprotein of VLDL?

ApoB-100.

What does ApoB-100 do?

Structural component of VLDL/LDL; ligand for LDL receptor for cell uptake.

Where are chylomicrons synthesized?

Intestinal epithelial cells (enterocytes).

What pathway do chylomicrons enter after assembly?

Lymphatic system (then thoracic duct to bloodstream), bypassing portal circulation due to size.

Where are VLDL synthesized?

Liver (hepatocytes).

What is VLDL secreted into?

The bloodstream.

Location of FA synthesis in cell?

Cytosol.

Organs where FA synthesis occurs?

Liver, adipose tissue, lactating mammary glands.

Carbon precursor for FA synthesis?

Acetyl-CoA (typically from glucose when in excess).

How does Acetyl-CoA exit mitochondria for FA synthesis?

As citrate (via citrate shuttle).

Where is citrate lyase active?

Cytosol.

What does citrate lyase produce?

Acetyl-CoA and oxaloacetate (OAA) from citrate.

Enzyme converting malate to pyruvate, yielding NADPH?

Malic enzyme (cytosolic).

Primary source of NADPH for FA synthesis?

Pentose Phosphate Pathway (PPP).

Secondary source of NADPH for FA synthesis?

Malic enzyme reaction.

What is NADPH functionally important for?

Reductive biosynthesis (e.g., FA synthesis, cholesterol synthesis).

Rate-limiting enzyme of FA synthesis?

Acetyl-CoA Carboxylase (ACC).

Cofactor for ACC?

Biotin.

Energy molecule for ACC activity?

ATP.

Allosteric activator of ACC?

Citrate (signals excess energy/substrate).

Hormonal activator of ACC?

Insulin (promotes dephosphorylation/activation).

Allosteric inhibitor of ACC?

Palmitoyl-CoA (feedback inhibition).

Kinase that inhibits ACC by phosphorylation?

AMP-activated protein kinase (AMPK).

Effect of insulin on ACC phosphorylation?

Dephosphorylation (activation).

Effect of glucagon on ACC phosphorylation?

Phosphorylation (inhibition).

Effect of epinephrine on ACC phosphorylation?

Phosphorylation (inhibition).

ACC converts Acetyl-CoA to what?

Malonyl-CoA.

Large enzyme complex for FA synthesis?

Fatty-acid synthase (FAS).

What carbon units does FA synthase add?

2-carbon units.

Donor of 2-carbon units to FA synthase?

Malonyl-CoA.

Final product of continuous FA synthase activity?

Palmitate (16:0), a 16-carbon saturated fatty acid.

Number of carbons in palmitate?

16 carbons.

Is palmitate saturated or unsaturated?

Saturated.

Subcellular location for FA elongation beyond palmitate?

Smooth ER.

What is elongating agent in SER?

Malonyl-CoA (donates 2-carbon units).

Cofactor required for FA elongation in SER?

NADPH.

Product of palmitate (16:0) elongation by 2 carbons?

Stearate (18:0).

Number of carbons in stearate?

18 carbons.

Enzyme introducing double bond at \Delta9 (e.g., converting stearate to oleate)?

\Delta9 desaturase (SCD1).

Substrate for \Delta9 desaturase?

Stearoyl-CoA (18:0).

One reductant for desaturation?

NADH (also NADPH).

One reactant for desaturation?

O_2 (molecular oxygen).

Electron acceptor in desaturation reactions?

Cytochrome b_5. (Part of an ER-localized mixed-function oxidase system).

Product of stearate (18:0) desaturation?

Oleate (18:1 \Delta9 ), an 18-carbon monounsaturated fatty acid.

Number of carbons in oleate?

18 carbons.

Number of double bonds in oleate?

One.

Position of double bond in oleate?

\Delta9 .

Essential \omega-6 fatty acid?

Linoleic acid.

Essential \omega-3 fatty acid?

Alpha-Linolenic acid (\alpha-Linolenic acid).

Humans cannot synthesize double bonds beyond which carbon position?

C9. This is why \omega-3 and \omega-6 fatty acids are essential.

Precursor for arachidonic acid?

Linoleic acid.

Arachidonic acid is a precursor for what potent mediators?

Eicosanoids (prostaglandins, leukotrienes, thromboxanes).

Examples of eicosanoids?

Prostaglandins, leukotrienes, thromboxanes.

Backbone molecule for TAG synthesis?

Glycerol-3-phosphate (G3P).

Other component for TAG synthesis?

Fatty acyl-CoA (which forms ester bonds with G3P).

Enzyme forming G3P from glycerol in liver?

Glycerol kinase (absent in adipose tissue).