Lipid Structure & Function

What are the structures and chemical properties of fatty acids?

• Lipids have three important roles in biology: (1) fatty acids and triacylglycerols serve as energy storage molecules; (2) glycerophospholipids and sphingolipids are major components of hydrophobic cell membranes; and (3) steroid hormones are signaling molecules in endocrine pathways, whereas eicosanoids function as signaling molecules in paracrine pathways.

• The most abundant fatty acids in nature are unbranched hydrocarbon chains that contain either reduced methylene groups (CH₂), called saturated fatty acids, or oxidized C=C bonds, called unsaturated fatty acids. Fatty acids with multiple C=C bonds are called polyunsaturated fatty acids.

• Free fatty acids are unesterified and have a carboxyl group at the C-1 carbon that is deprotonated and charged at pH 7 (pK_a of the carboxyl group is ~4.8); biological free fatty acid conjugate bases are named with the suffix -ate, as in palmitate and oleate.

• The common names of fatty acids indicate how or where the fatty acid was discovered. For example, palmitate was first isolated from palm oil, and linoleate was isolated from flaxseed. Humans require at least three essential fatty acids in their diet: the polyunsaturated fatty acids linoleate, α-linolenate, and arachidonate.

• The number and configuration of C=C bonds in unsaturated fatty acids affect the melting points of fatty acid mixtures, with long-chain saturated fatty acids having a higher melting point than long-chain unsaturated fatty acids because the saturated fatty acids experience stronger intermolecular interactions.

• The melting points of lipid mixtures can be increased by converting unsaturated fatty acids into saturated fatty acids by using a commercial process called hydrogenation. The hydrogenation process is not 100% efficient, giving rise to both fully saturated fatty acids and fatty acids containing C=C bonds with the trans configuration. Consumption of large amounts of trans fats is associated with an increased risk of cardiovascular disease owing to elevated levels of serum LDL.

• Carbons in fatty acids are numbered from the carboxylic acid end, with the carboxyl carbon being C-1. Any C=C bonds present are denoted as superscript numerals associated with the symbol Δ. For example, palmitate is a saturated C16 fatty acid (16:0), whereas α-linolenate is an unsaturated C18 fatty acid with three cis C=C bonds at C-9, C-12, and C-15, written as cis-18:3(Δ^9,12,15).

• Fatty acids can also be numbered from the methyl carbon (the ω-carbon). Polyunsaturated fatty acids with the most distal C=C bond from the carboxyl group positioned three carbons away from the ω-carbon are called ω-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The same nomenclature can be used to describe the ω-6 fatty acids linoleate and arachidonate.

What are the structures and functions of waxes and neutral lipids?

• Methods used to isolate and characterize lipids depend on techniques in lipid biochemistry; lipidomics is a collection of organic chemistry protocols based on thin layer chromatography, gas phase chromatography, and mass spectrometry.

• Waxes are an abundant lipid found in nature, consisting of long-chain fatty alcohols linked to long-chain fatty acids to generate wax esters. The melting points of most waxes are higher than ambient temperature, making them solids in their biological context.

• Some wax esters, like those found in jojoba beans and sperm whale oil, are liquids under physiologic conditions, owing to the incorporation of unsaturated fatty acids.

• Triacylglycerols consist of three fatty acids esterified to glycerol, which makes them neutral lipids because the carboxyl groups are neutralized. In a Fischer projection, the middle carbon is designated the sn-2 position, using the stereospecific numbering system, whereas the top and bottom carbons are designated the sn-1 and sn-3 positions, respectively.

How do triacylglycerols function as energy storage lipids?

• The primary function of triacylglycerols is energy storage. In animals, triacylglycerols are stored in fat cells called adipocytes; in plants, triacylglycerols are stored in the seeds and provide an oxidizable energy source for the developing embryo after germination.

• Two reasons why triacylglycerols are the primary form of energy storage instead of glucose-derived polymers are (1) fatty acids are at a higher reduction state than glucose and therefore yield more energy (electrons for redox reactions) for the same number of carbons upon oxidation; and (2) triacylglycerols are not solvated by water and therefore have less mass for the same amount of stored energy.

• Triacylglycerols are obtained from the diet, primarily from digesting animal fat and nuts in the small intestine, and are synthesized in the liver.

• Triacylglycerols are transported through the blood as components of lipoprotein complexes, which can be very large chylomicrons produced in intestinal epithelial cells or small very-low-density lipoprotein (VLDL) particles synthesized and exported by liver cells.

• Adipocytes hydrolyze stored triacylglycerols in response to glucagon and epinephrine signaling and release fatty acids and glycerol into the circulatory system. Fatty acids are transported through the circulatory system by a carrier protein called albumin.

• Dietary triacylglycerols are hydrolyzed in the small intestine by lipase enzymes such as pancreatic lipase that releases two free fatty acids and sn-2 monoacylglycerol (2-MAG). Free fatty acids and glycerol enter the intestinal epithelial cells, where they are resynthesized into triacylglycerols and then exported to the lymphatic system as components of chylomicron lipoproteins.

• The biosynthesis of triacylglycerols in animals uses acetyl-CoA produced by the degradation of carbohydrates and proteins to generate palmitate in the cytosol, which is then esterified to a glycerol backbone to form triacylglycerols and exported as VLDL particles.

• Lipoprotein particles contain proteins on the surface that facilitate fatty acid delivery to peripheral tissues through binding and activation of lipoprotein lipase on the surface of endothelial cells. The fatty acids diffuse into nearby adipose and muscle cells, whereas the glycerol travels through the blood to the liver.

What are the three major types of lipids in cell membranes?

• The outer monolayer of the plasma membrane contains mostly phosphatidylcholine and sphingolipids, whereas the inner monolayer contains mostly glycerophospholipids. The total cholesterol content of the outer monolayer and that of the inner monolayer are similar.

• The most abundant lipids in membranes are phospholipids (glycerophospholipids and sphingomyelin) followed by cholesterol and sphingoglycolipids. Glycerophospholipids represent about half of all membrane lipids in eukaryotic cell membranes, with sphingolipids and cholesterol contributing to the other half.

• Glycerophospholipids are derived from phosphatidate and include the membrane phospholipids phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol.

• Many types of snake venom contain phospholipase enzymes that hydrolyze glycerophospholipids to release free fatty acids that destroy plasma cell membranes. If a snakebite is left untreated, death may occur from massive internal bleeding.

• Sphingolipids are derived from the biomolecule sphingosine (which is synthesized by linking serine to the carboxyl group of palmitate) and one fatty acid. There are two types of sphingolipids: the sphingophospholipids, represented by sphingomyelin, and the sphingoglycolipids, which are called cerebrosides and gangliosides.

• Defects in sphingolipid metabolism lead to three related hereditary disorders: Tay–Sachs disease, Fabry disease, and Niemann–Pick disease. All three genetic diseases are caused by the buildup of metabolic precursors, which leads to severe neuronal defects and death.

• Cholesterol contains a rigid, four-ring structure that disrupts the packing of glycerophospholipids and sphingolipids when inserted into membranes.

• Biochemical studies suggest that regions of the plasma membrane are transiently organized into “lipid rafts” that contain high levels of cholesterol transmembrane proteins, such as ligand-activated receptor proteins and GPI-anchored proteins.

How are steroid hormones synthesized from cholesterol?

• Cholesterol is the precursor to steroids (mineralocorticoids, glucocorticoids, progesterones, androgens, and estrogens) and vitamin D. Eicosanoids are derived from the ω-6 fatty acid arachidonate, a polyunsaturated fatty acid that is converted into prostaglandins, prostacyclin, thromboxanes, and leukotrienes.

• Steroids are potent endocrine hormones with critical roles in cell development, reproductive biology, and organismal physiology. Steroid signaling is mediated by steroid binding to nuclear receptor proteins that function as transcription factors.

• Many of the enzymes involved in steroid biosynthesis (steroidogenesis) are hydroxylases, of which one type is the cytochrome P450 monooxygenases. Steroidogenesis begins with removal of the side chain attached to the D ring of cholesterol to generate pregnenolone, the biosynthetic precursor to all animal steroids.

• Mineralocorticoids and glucocorticoids are synthesized in the adrenal glands, whereas estrogen is synthesized in the female ovaries, testosterone in the male testes, and progesterone in the corpus luteum in pregnant females. The adrenal glands also synthesize androgens, which is how females acquire testosterone for estradiol production.

• Vitamin D is derived from cholesterol and was discovered as a nutritional supplement that could be added to the diet to treat the debilitating bone disease rickets. Only ~10% of vitamin D in the human body is acquired from the diet; the rest comes from sunlight conversion of 7-dehydrocholesterol in skin cells.

How do NSAIDs reduce inflammation by inhibiting cyclooxygenases?

• Eicosanoids are a group of signaling molecules derived from C20 polyunsaturated fatty acids such as arachidonate and are released from the membrane by phospholipases and modified by mitochondrial enzymes.

• Eicosanoids are paracrine hormones that are produced by cells at their sites of action and have half-lives of only a few minutes. The four major classes of arachidonate-derived eicosanoids are prostaglandins, prostacyclin, thromboxanes, and leukotrienes, which mediate cell signaling by activating G protein–coupled receptors on target cells.

• The synthesis of prostaglandins, prostacyclin, and thromboxanes requires cyclooxygenation of arachidonate by either cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2) to generate the precursor prostaglandin H₂. The enzyme lipoxygenase generates leukotrienes directly from arachidonate.

• Many of the eicosanoid signaling molecules derived from prostaglandin H₂ contribute to the severity of inflammatory responses, and therefore drugs that inhibit prostaglandin H₂ synthesis function as anti-inflammatory agents.

• The most commonly used inhibitors of prostaglandin H₂ synthesis are called nonsteroidal anti-inflammatory drugs (NSAIDs) to distinguish them from glucocorticoids, such as prednisone, which are also used to decrease inflammation. NSAIDs include aspirin (acetylsalicylate), ibuprofen, and naproxen.

• Human COX-1 and COX-2 are isoenzymes that have similar catalytic activities but distinct physiologic functions. COX-1 produces prostaglandins that stimulate mucin secretion and protect the lining of the stomach from low pH, whereas COX-2 produces prostaglandins that cause the swelling, pain, and fever associated with inflammation.

• Aspirin, ibuprofen, and naproxen are nonselective COX-1/COX-2 inhibitors because they bind to and inhibit both COX-1 and COX-2 enzymes, which reduces inflammation by inhibiting COX-2 but increases the risk of developing bleeding ulcers through inhibition of COX-1.

• Selective COX-2 inhibitors have improved anti-inflammatory properties with decreased risk of ulcers because they bind to and inhibit COX-2 without affecting COX-1.