Metabolism of Lipids: Fatty Acids and Eicosanoids

Metabolism of Lipids (Fatty Acids & Eicosanoids)

Biosynthesis of Fatty Acids

• Fatty acids are synthesized from acetyl CoA and oxidized to acetyl CoA
• Fatty acid synthesis occurs in the cytosol, while fatty acid oxidation occurs in the mitochondria
• Major sites of lipogenesis: liver, adipose tissue, mammary gland, kidney, lung, and brain
• Free palmitate is the end product of fatty acid synthesis, and all other fatty acids are made by its modification

Fatty Acid Activation

• Fatty acid activation involves the conversion of free fatty acids to acyl-CoA, catalyzed by acyl-CoA synthetase

Enzymes Involved in Fatty Acid Synthesis

• Malonyl-CoA is formed from acetyl-CoA through the action of acetyl-CoA carboxylase (ACC)
• Fatty acid synthase (FASN) is a multienzyme complex that catalyzes the synthesis of fatty acids
• FASN has 7 enzymes and a protein (Vitamin B5 - Pantothenic acid)

Rate-Limiting Step in Fatty Acid Synthesis

• The formation of Malonyl-CoA is the rate-limiting step in fatty acid synthesis
• Acetyl-CoA carboxylase (ACC) is activated by citrate, insulin, and dephosphorylation, and inactivated by glucagon/epinephrine and phosphorylation

Fatty Acid Synthesis: Lipogenesis

• Fatty acid synthesis involves the sequential addition of 2-carbon units from malonyl-CoA to the activated end of the chain
• The process is repeated seven times to form a 16-carbon saturated palmitate
• Palmitate is the final product of fatty acid synthase complex

Sources of NADPH

• Pentose phosphate pathway is the chief source of NADPH for fatty acid synthesis
• Other sources of NADPH include the conversion of malate to pyruvate by malic enzyme and the extramitochondrial isocitrate dehydrogenase reaction

Fate of Palmitate

• Palmitate is activated to acyl-CoA before it can proceed to any metabolic pathways
• Palmitoyl-CoA can be esterified to acylglycerols, cholesteryl esters, or undergo chain elongation and desaturation

Chain Elongation

• Fatty acid elongation occurs in the endoplasmic reticulum
• Elongases use malonyl-CoA as the acetyl donor and NADPH as the reducing power
• Palmitoyl-CoA is converted almost exclusively to stearate (18:0)

Formation of Monoenoic Acids

• Fatty acid desaturation introduces double bonds in the fatty acid chain
• Δ9 desaturase introduces a double bond in the Δ9 position
• Monoenoic acids are formed in the endoplasmic reticulum

Formation of Polyunsaturated Fatty Acids (PUFA)

• PUFA are formed through the addition of double bonds to monoenoic acids
• In mammals, double bonds can only be added to the proximal half of the fatty acyl-CoA chain
• There are 4 distinct desaturases, each with a different specificity: Δ9, Δ6, Δ5, and Δ4

Clinical Aspect

• Essential fatty acid deficiency can lead to skin disorders, hair loss, and reproductive problems
• The addition of linoleic, α-linolenic to the diet can treat essential fatty acid deficiency

Nutritional State Regulates Lipogenesis

• High carbohydrate diet, well-fed state, insulin, and sucrose increase lipogenesis
• Restricted caloric diet, high-fat diet, deficiency of insulin, glucagon, and epinephrine decrease lipogenesis

Eicosanoids

Definition and Roles

• Eicosanoids are active compounds involved in inflammation and reproductive function
• They act as local hormones affecting the cells that produce them or neighboring cells

Sources of Arachidonic Acid

• Arachidonic acid is released from cellular stores through the action of phospholipase A2 or C
• Dietary sources of arachidonic acid include linoleic (ω6) and α-linolenic acids (ω3)

Metabolism of Eicosanoids

• Cyclooxygenase pathway forms prostaglandins and thromboxanes
• Lipoxygenase pathway forms leukotrienes and lipoxins

Cyclooxygenase Pathway

• Cyclooxygenase (COX) has two activities: cyclooxygenase and peroxidase
• COX-1 and COX-2 are the two isoenzymes of COX

Lipoxygenase Pathway

• Lipoxygenase incorporates O2 into a carbon forming a hydroperoxy group
• The hydroperoxy group is further converted to an epoxide or a hydroxyl group

Functions of Eicosanoids

• Prostaglandins, thromboxanes, leukotrienes, and lipoxins have various functions, including vasodilation, vasoconstriction, platelet aggregation, and bronchoconstriction

Pharmacology

• Glucocorticoids inhibit phospholipase A2
• Aspirin inhibits cyclooxygenase
• NSAIDs (ibuprofen, naproxen, mefenamic acid) inhibit cyclooxygenase
• COXIBs (celecoxib) selectively inhibit COX-2
• Zileuton (Zyflo) inhibits 5-lipoxygenase
• Montelukast blocks the activation of LTC4, LTD4, LTE4

This quiz covers the biosynthesis of fatty acids and eicosanoids, including the effects of diet and nutrition on fatty acid synthesis and the impact of pharmacologic agents on eicosanoid metabolism.