Fatty acids and triglycerides (the storage form of fatty acids) constitute an energetic reserve in the body. Most of the cells can synthesize fatty acids, but there are essential fatty acids such as linoleic acid, α-linoleic, and arachidonic acid that cannot be synthesized. Arachidonic acid is made from linoleic acid and is the precursor for prostaglandins, thromboxanes, and leukotrienes that participate in different pathways such as the inflammatory response. Drugs that block the enzyme cyclo-oxygenase and prostaglandin synthesis such as acetaminophen, ibuprofen, and acetylsalicylate provide pain relief. Fatty acids can directly mediate transcriptional responses, acting as ligands for peroxisome proliferator-activated receptors, a family of NHRs. In addition, there are specific GPCR receptors such as GPR40 and GPR120 activated by medium- or long-chain fatty acids. GPR43 is activated by short-chain fatty acids and is highly abundant in leukocytes.

Fatty Acid Synthesis

In the mitochondrial matrix, acetyl-CoA is generated from pyruvate and is the precursor for fatty acid synthesis. Acetyl-CoA cannot cross the mitochondrial membrane; thus acetyl-CoA condenses with oxaloacetate (first reaction in the TCA cycle) to form citrate that is exchanged into the cytoplasm through TCA translocases. Once in the cytoplasm, citrate is converted to acetyl-CoA by ATP citrate lyase. The rate-limiting reaction of fatty acid synthesis is the carboxylation of acetyl-CoA to form malonyl CoA, which is catalyzed by acetyl CoA carboxylase (ACC). Malonyl CoA is a potent inhibitor of fatty acid oxidation. ACC is allosterically regulated by citrate to form active enzyme polymers, which are depolymerized by the end product of fatty acid synthesis: long-chain fatty acids. Growth factors positively control ACC dephosphorylation. In contrast, catecholamines result in the phosphorylation and inhibition of ACC via PKA. Fatty acids are synthesized in the cytoplasm by a multifunctional enzyme, FAS. Two of these functional domains are the acyl carrier protein and the condensing enzyme (CE). After completion of the different rounds of synthesis, the palmityl group is transferred to CoASH. In macrophages, LPS activates lipogenesis through activation of sterol regulatory element–binding protein (SREBP), a key transcriptional mediator of cholesterol and fatty acid synthesis.

Fatty Acid Oxidation

 Fatty acids are “charged” before oxidation to form acyl-SCoA, a cytoplasmic reaction catalyzed by the enzyme fatty acyl-CoA synthetase. However, fatty acid β-oxidation occurs in the mitochondrial matrix, and charged fatty acids must first be conjugated to carnitine to cross the mitochondrial membrane. This transport is carried out by the carnitine acyltransferases I and II. These enzymes constitute a rate-limiting step for β-oxidation of fatty acids and are allosterically regulated by malonyl CoA, allowing the cell to avoid a futile cycle of fatty acid synthesis and breakdown. Inside the mitochondria, acyl-CoA under goes a cycle of reactions removing acetyl-CoA from the main chain. This acetyl-CoA is then processed through the TCA cycle.

Cholesterol

Cholesterol is an important component of cellular membranes and a substrate to produce steroid hormones. Free cholesterol is tightly controlled in cells through synthesis, storage, and transport. Excess cholesterol in cells is secreted through reverse cholesterol transport or stored in the cytoplasm as cholesterol ester, produced by Acy Coa: cholesterol acyltransferase located in the ER. Cholesterol is transported in the plasma by lipoproteins, including chylomicrons and very-low-density lipoprotein (VLDL). The main sources of cellular cholesterol for hematopoietic cells are the cholesterol-rich lipoprotein, low-density lipoprotein (LDL), and de novo synthesis from acetyl-CoA. The rate-limiting step for cholesterol synthesis is catalyzed by hydroxymethylglutaryl (HMG)-CoA reductase, the direct target of cholesterol-lowering statin drugs, and converts HMG-CoA to mevalonic acid. Cellular cholesterol levels are sensed in the ER through the SREBP transcription factor, which directly controls most the enzymes in cholesterol synthesis as well as LDL transport. Excess of LDL becomes oxidized and taken by macrophages, a main cause of atherosclerosis. The SREBP pathway is also important for T-cell activation under antigenic challenge, because its activation favors cholesterol synthesis and transport, which is used for membrane biogenesis and cell proliferation in the activated T cell.

Phospholipids

 Phospholipids contain a hydrophilic head with a glycerol phosphate group that is esterified to a hydroxyl group of serine, choline, or ethanolamine, and two hydrophobic tails that are fatty acids esterified to two of the carbons of glycerol phosphate. They are main constituents of cellular membranes and form the lipid bilayer. Phospholipid synthesis takes place in the ER membrane, and they are delivered to cellular membranes. Some types of phospholipids also form part of signaling transduction as substrates for phospholipase C. Phospholipids are unequally distributed among organelle membranes and are also asymmetrically localized between the two sides of the bilayer. For example, phosphatidylcholine (PS) is enriched in the inner part of the plasma membrane and becomes exposed during cell death and targeted through the macrophage’s PS receptor. The synthesis of phospholipids starts with DAG or cytidine diphosphate (CDP)-DAG that is formed from phosphatidic acid, which is made from the glycolytic intermediate glycerol-3-phosphate or dihydroxyacetone phosphate. Specific enzymes synthesize PS, phosphatidylethanolamine, and phosphatidylserine. PS is made via the Kennedy pathway via CDP-choline. A potent phospholipid that plays important roles in leukocyte chemotaxis, macrophage oxidative burst, and platelet aggregation is the platelet-activating factor (acetyl-glyceryl-ether-phosphorylcholine).

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مواضيع ذات صلة

The Chemical Nature of RNA Differs From That of DNA

DNA Provides A Template For Replication & Transcription

DNA Can be Reversibly Denatured & Specifically Renatured, Both in the Test Tube & in Living Cells

DNA Contains Four Distinct Deoxynucleotides

Overproduction of Pyrimidine Catabolites

Disorders of Purine Metabolism

Biochemical Characteristics and Biological Function of Cardiac Natriuretic Peptides

The Deoxyribonucleosides of Uracil & Cytosine are Salvaged

Biosynthesis of Pyrimidine Nucleotides

Hepatic Purine Biosynthesis is Stringently Regulated

Inosine Monophosphate (IMP) is Synthesized From Amphibolic Intermediates

DNA & RNA are Polynucleotides