Cholesterol and Omega-3 Fatty Acids Quiz

Unsaturated Fatty Acids

• Eicosanoids are compounds derived from eicosanoic acid (20 carbon atoms), which is formed from essential fatty acids.
• Long-chain unsaturated fatty acids (C20, C22, C24) are derived from oleic, linoleic, and linolenic acids.
• Examples of unsaturated fatty acids include palmitoleic acid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid, and nervonic acid.
• Essential fatty acids (linoleic acid and linolenic acid) cannot be synthesized by the body and must be obtained through diet.
• Omega-3 fatty acids, such as alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are important.
• These fatty acids are precursors of prostaglandins.
• Eicosanoids have various functions, including prostaglandin and leukotriene synthesis, structural integrity of mitochondrial membranes, and synthesis of retina, cerebral cortex, and sperm.

Other Functions

• Regulate inflammation and allergies.
• Some elevate body temperature (producing fever).
• Affect immune responses.
• Some prostaglandins stimulate smooth muscle contraction during menstruation and labor, regulating pregnancy and birth.
• Contribute to the perception of pain.
• Affect blood flow to tissues, controlling blood pressure.

Dietary Precursor of Prostaglandins

• The dietary precursor of prostaglandins is linoleic acid.
• It is elongated and desaturated to form arachidonic acid (20:4(5,8,11,14)), the immediate precursor.
• Different subfamilies of eicosanoids exist, prominently including prostaglandins, thromboxanes, leukotrienes, lipoxins, resolvins, and eoxins (further study required).

Inhibition of Prostaglandin Synthesis

• Prostaglandin synthesis can be inhibited by various compounds.
• Cortisol inhibits phospholipase A2 and COX-2 activity.
• Aspirin, indomethacin, and phenylbutazone (NSAIDs) inhibit both COX-1 and COX-2, preventing PGH2 synthesis.
• Celecoxib and similar inhibitors are specific for COX-2, reducing inflammation.

Synthesis of Leukotrienes

• Arachidonic acid is converted to various hydroperoxy acids by lipoxygenase enzymes.
• Neutrophils contain 5-lipoxygenase, converting arachidonic acid to 5-hydroxy-6,8,11,14 eicosatetraenoic acid (5-HPETE).
• 5-HPETE is converted into leukotrienes which mediate allergic response and inflammation.
• Inhibitors of 5-lipoxygenase and leukotriene synthesis are used to treat asthma.

Role of Prostaglandins in Platelet Homeostasis

• Thromboxane A2 (TXA2) is produced by activated platelets.
• It promotes platelet adherence, aggregation, and vascular smooth muscle contraction, thus facilitating blood clot formation.
• Leukotriene D4 induces contraction of the airway smooth muscle, causing asthma attacks.

Cholesterol

• Cholesterol is synthesized by all human tissues from LDL and HDL, and diet.
• Synthesis begins from acetyl-CoA in the cytoplasm and requires NADPH from the PPP.
• Cholesterol is vital for cell membranes, bile acid synthesis, steroid hormone production, and vitamin D synthesis.
• Cholesterol enters the liver's cholesterol pool from dietary cholesterol and extrahepatic and liver synthesis.
• Cholesterol is eliminated from the liver as free cholesterol in bile or converted to bile salts, secreted into the intestinal lumen.
• Gradual accumulation of cholesterol in blood vessels leads to plaque formation, causing atherosclerosis, and increased risk of coronary artery disease.

Cholesterol Structure

• Cholesterol is a very hydrophobic compound.
• It consists of four hydrocarbon rings (A, B, C, and D), plus an eight-carbon branched hydrocarbon chain attached to C-17 of the D ring.
• Ring A has a hydroxyl group at C-3, and ring B has a double bond.

Cholesterol Esters (CE)

• Most cholesterol exists in an esterified form (with a fatty acid at C-3), making it more hydrophobic than free cholesterol.
• Due to hydrophobicity, cholesterol and its esters need protein association as lipoproteins to be transported.

Cholesterol Synthesis

• Cholesterol is synthesized in the cytoplasm with acetyl CoA as the starting material and NADPH assistance.
• The first two steps produce 3-hydroxy-3-methylglutaryl CoA (HMG CoA).
• A third acetyl CoA joins, leading to HMG CoA, which is a six-carbon compound.

Mevalonic Acid Synthesis

• The reduction of HMG CoA to mevalonic acid is catalyzed by HMG CoA reductase.
• This is the rate-limiting step in cholesterol synthesis.
• The process happens in the cytosol, uses two molecules of NADPH, and releases CoA.

Cholesterol Synthesis Pathway

• The next steps in cholesterol synthesis involve farnesyl PP, squalene, and lanosterol, ultimately resulting in cholesterol production.
• Cholesterol then leads to steriod hormones, vitamin D, and bile acids production.

Regulation of Cholesterol in Hepatocytes

• HMG CoA reductase, the rate-limiting enzyme, is the major point of control in cholesterol biosynthesis.
• Cholesterol itself inhibits HMG CoA reductase.
• Insulin activates HMG CoA reductase, increasing cholesterol synthesis; glucagon inhibits it, decreasing synthesis.
• LDL and chylomicron cholesterol in cells reduce HMG CoA reductase transcription, lowering synthesis.
• Drugs like simvastatin, lovastatin, and mevastatin are HMG CoA reductase inhibitors, lowering cholesterol.

HMG CoA Reductase Regulation

• HMG CoA reductase activity is controlled by phosphorylation/dephosphorylation.
• Protein kinases deactivate the enzyme, decreasing cholesterol synthesis; phosphoprotein phosphatases activate it, increasing synthesis.
• ATP reduces cholesterol synthesis by converting the active form of HMG CoA reductase to inactive.

Additional Home Work

• Resolvins and eoxins: function.
• Calcium's role in thrombus formation.
• Comparison of PG E2 and PGF2 actions on uterine smooth muscles.
• Insulin and glucagon in cholesterol and palmitate synthesis.
• Protein kinase and phosphoprotein phosphatase in cholesterol synthesis and palmitate.