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