Fatty Acids and Lipids

Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty acids are integral building blocks of lipids, and can be classified as unsaturated or saturated based on the presence/absence of carbon-carbon double bonds within their nonpolar chains. Eicosanoids are a family of cell-signaling molecules with important physiologic properties derived from the fatty acid, arachadonic acid. In addition, combining fatty acids with different bases, including glycerol, phosphate, and shingosine, results in different lipids with varied functions within the human body. Glycerolipids (triacylglycerols) are important for energy storage and thermal insulation. Glycerophospholipids and sphingolipids are essential constituents of cellular plasma membranes. Another group of lipids is based off of isoprenoids, which are the building blocks of sterols (such as cholesterol). Altered levels of lipids (both an overabundance or deficiency) can result in many potential disease processes.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Fatty Acids

Overview

  • Characterized by a carboxyl group (COOH) and an aliphatic chain of carbon atoms, which end with a methyl group (CH3).
  • May be amphiphilic (amphipathic) molecules: 
    • Made up of 2 portions: polar (interacts with water) and nonpolar (does not interact with water) 
    • Mainly used as molecules for energy storage
    • Form major components of the plasma membrane
  • Categorized based on saturation (number of double bonds between carbons): 
    • Saturated:
      • The most common fatty acids in cells
      • Do not have carbon-to-carbon double bonds
      • ↑ Length → ↑ melting point
      • Desaturation → ↓ melting point
      • Examples include lauric acid, myristic acid, stearic acid, palmitic acid, and arachidic acid.
    • Unsaturated:
      • Monounsaturated→ 1 double bond (e.g., oleic acid)
      • Polyunsaturated→ 2 or more double bonds (e.g., essential fatty acids like linoleic acid and linolenic acid)
      • Eicosanoids Eicosanoids Eicosanoids are cell-signaling molecules produced from arachidonic acid. With the action of phospholipase A2, arachidonic acid is released from the plasma membrane. The different families of eicosanoids, which are prostaglandins (PGs), thromboxanes (TXA2s), prostacyclin (PGI2), lipoxins (LXs), and leukotrienes (LTs), emerge from a series of reactions catalyzed by different enzymes. Eicosanoids: derived from polyunsaturated fatty acids
      • Prostanoids, leukotrienes, and lipoxins
  • Biological fatty acids: 
    • Naturally occurring
    • Most naturally occurring unsaturated fatty acids have double bonds in the cis configuration.
      • cis: if the 2 R groups are on the same side of the carbon-to-carbon double bond
      • trans: if the 2 R groups are on opposite sides of the carbon-to-carbon double bond 
  • Trans fats: 
    • Contain double bonds in the trans configuration 
    • Produced after a chemical alteration of food, during hydrogenation, or “hardening,” of natural oils in the manufacture of margarine
    • An additional small contribution (2‒7%) comes from the ingestion of ruminant due to the action of microorganisms in the rumen ( stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach).
    • Consumption is associated with ↑ risk of diseases, including cardiovascular disease and diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus.
    • “Soft” margarine is low in trans fatty acids, or contains none at all.

Nomenclature of fatty acids

  • Based on functional aspects and the nature of the backbones:
    • Glycerol is a tertiary alcohol.
    • Sphingosine is an unsaturated amino alcohol.
    • Isoprene is an unsaturated hydrocarbon.
  • Genevan system:
    • Saturated:
      • Suffix: -anoic
      • Contains double bonds
    • Unsaturated:
      • Suffix: -enoic
      • Contains single and double bonds
  • Delta numbering system: Carbons are counted from the COOH towards the CH3 (left → right).
  • Omega numbering system: Carbons are counted from the CH3 towards the COOH (right → left) → gives rise to omega (ω) fatty acids
Table: Examples of saturated fatty acids
Name Number of carbon atoms Occurrence
Lauric acid 12 Spermaceti, cinnamon, palm kernel, coconut oil, laurels, and butter
Myristic acid 14 Nutmeg, palm kernel, coconut oil, myrtles, and butter
Palmitic acid 16 Common in all animal and plant fats
Table: Unsaturated fatty acids of physiologic and nutritional significance
Bonds Number of carbons and position of double bonds Family Common name Occurrence
Monoenoic acids (1 double bond) 18:1;9 ω9 Oleic acid Possibly the most common fatty acid in natural fats (particularly high in olive oil)
Dienoic acids (2 double bonds) 18:2;9,12 ω6 Linoleic acid Corn, peanut, cottonseed, soybean, and many plant oils
Trienoic acids (3 double bonds) 18:3;6,9,12 ω6 γ-linolenic acid Found in some plants (e.g., oil of evening primrose, borage oil); a minor fatty acid in animals
18:3;9,12,15 ω3 α-linolenic acid Frequently found with linoleic acid (particularly in linseed oil)
Tetraenoic acids (4 double bonds) 20:4;5,8,11,14 ω6 Arachidonic acid Found in animal fats; an important component of phospholipids in animals
Pentanoic acids (5 double bonds) 20:5;5,8,11,14,17 ω3 Timnodonic acid Important component of fish oils, egg, cod liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, mackerel, menhaden, and salmon oils
Hexanoic acids (6 double bonds) 22:6;4,7,10,13,16,19 ω3 Cervonic acid Fish oils, algal oils, and phospholipids in the brain

Glycerolipids and Glycerophospholipids

Glycerolipids and glycerophospholipids are glycerol-based fatty acids ubiquitous in human cells. Glycerolipids and glycerophospholipids function as structural components of plasma membranes and as storage for energy.

Glycerolipids (triacylglycerols/triglycerides)

  • 1 molecule of glycerol (polarized) + 3 fatty acids
  • Linked by ester bonds (between a -OH and a COOH group)
  • Degree of unsaturation determines if fat or oil:
    • Fats are solid at room temperature.
    • Oils are liquid at room temperature.
  • Provides thermal insulation
  • The main storage forms of fatty acids, as adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue; provide energy supply and thermal insulation
Structure of a triacylglycerol molecule

Structure of a triacylglycerol molecule:
See its glycerol backbone and its constituent fatty acids. Linolenic acid is more susceptible to oxidation than the other 2 fatty acids due to its extra double bonds. This decomposition causes the fat to become rancid, i.e., to have an unpleasant taste or smell.

Image by Lecturio.

Glycerophospholipids (phosphoglycerides)

  • A glycerol backbone (polarized) + 2 fatty acids + 1 phosphate group (PO4)
  • Major components (and the main lipid constituents) of the plasma membrane (lipid bilayer)
  • Possess a hydrophobic tail and a hydrophilic head
  • Lecithins are an example of glycerophospholipid:
    • Amphiphilic
    • Contain choline, phosphatidylcholine, and phosphatidylethanolamine
    • The most abundant phosphoglycerides in the body
    • Represent a large store of choline for other physiologic functions (e.g., acetylcholine)
    • Constitute the lipidic component of pulmonary surfactant
Lipid arrangements

Lipid arrangements:
Lipids, like glycerophospholipids, contain a polar head and nonpolar tail (A).
A lipid bilayer is composed of lipid molecules with their heads facing outward, and tails inward (B).
This arrangement is usually preferred by glycerophospholipids because their hydrophobic tails are often too bulky for the spherical shape of a micelle (C).

Image by Lecturio.

Sphingolipids

Sphingolipids are a heterogeneous family of lipids sharing the characteristic sphingoid base backbone:

  • Composed of ceramide (sphingosine + fatty acid) + another molecule (“R”) linked to the sphingosine
  • Amphipathic and amphiphilic (both hydrophobic and hydrophilic properties)
  • A major component of the lipid bilayer
  • Several molecules bind to sphingosine producing molecules with different functions:
    • Sphingomyelin:
      • Ceramide ⍆ a phosphate group + choline
      • Found in the myelin sheath of nerve cells
    • Cerebroside:
      • Ceramide + monosaccharide (a single sugar)
      • Important components of nerve cell membranes
    • Ganglioside:
      • Ceramide + complex carbohydrate
      • Complex carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates

Isoprenoids and Sterols

Sterols and isoprenoids, which form sterols, are an important group of fatty acids used as part of the cellular plasma membrane and as bile acids, which help absorb fats.

Isoprenoids

  • Building blocks of sterols 
  • Contain 5 carbons
  • Examples:
    • Dimethylallyl pyrophosphate
    • Isopentenyl pyrophosphate

Sterols

  • A subgroup of steroid molecules
  • Phytosterols in plants (e.g., ergosterol)
  • Zoosterols in animals (e.g., cholesterol)
  • Cholesterol:
    • The most abundant zoosterol
    • Dietary source (synthesized in the body or stored)
    • Bonds to a fatty acid → cholesteryl ester and stored in the lipid bilayer
    • Cholesterol ester storage form
    • Component of:
      • Plasma cell 
      • Mitochondria 
      • Golgi complex 
      • Nuclear membranes

Clinical Relevance

  • Coagulation disorders: Eicosanoids Eicosanoids Eicosanoids are cell-signaling molecules produced from arachidonic acid. With the action of phospholipase A2, arachidonic acid is released from the plasma membrane. The different families of eicosanoids, which are prostaglandins (PGs), thromboxanes (TXA2s), prostacyclin (PGI2), lipoxins (LXs), and leukotrienes (LTs), emerge from a series of reactions catalyzed by different enzymes. Eicosanoids are compounds that are derived from eicosa (20-carbon) polyenoic fatty acids. They comprise leukotrienes, lipoxins, and prostanoids, which include prostaglandins, prostacyclins, and thromboxanes. The molecules play vital roles as inflammatory markers. Thromboxanes are important for clotting within coagulation cascades and for platelet adhesion. Nonsteroidal anti-inflammatory drugs (NSAIDS) inhibit cyclooxygenases by competing with arachidonate.
  • Prostanoids: can be utilized as pharmaceutical agents. Uses include the prevention of conception, induction of labor Labor Labor is the normal physiologic process defined as uterine contractions resulting in dilatation and effacement of the cervix, which culminates in expulsion of the fetus and the products of conception. Normal and Abnormal Labor at term, termination of pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, prevention of gastric ulcers, control of inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and blood pressure, and relief of asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma and nasal congestion. PGD2 promotes sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep. Prostaglandins increase cAMP in platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets, thyroid, corpus luteum, fetal bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones, adenohypophysis, and lung, but reduce cAMP in renal tubule cells and adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or "brite" adipose tissue, which is a transitional form. Adipose Tissue.
  • Leukotrienes and lipoxins: these eicosanoids regulate many disease processes. Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of leukotrienes C4, D4, and E4. Properties include potent constriction of bronchial airways, increased vascular permeability, chemoattraction, and leukocyte activation during hypersensitivity reactions (such as asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma). Lipoxins are anti-inflammatory/counterregulatory compounds (chalones) of the immune response, and have vasoactive functions.
  • Polyketides: molecules created by organisms in a similar fashion to fatty acids (utilizing similar enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes and acyl-CoA). These products have a wide array of pharmaceutical properties, and have been used for antibacterial, antifungal, immunosuppressive, and antitumor applications. Notable polyketide medications include erythromycin, tetracycline, amphotericin, tacrolimus, and anthramycin.
  • Neonatal Respiratory Distress Syndrome Neonatal Respiratory Distress Syndrome Respiratory distress syndrome (RDS), also known as hyaline membrane disease, is caused by the lack of adequate pulmonary surfactant production in an immature lung. The syndrome is most commonly seen in preterm infants. Neonatal Respiratory Distress Syndrome: In premature births, a low quantity and quality of natural surfactants cause the collapse of alveoli. Composed of 70% glycerophospholipid (specifically the phosphatidylcholine species), natural surfactant reduces surface tension within the alveoli, allowing for improved oxygen exchange. The early administration of pulmonary surfactant is important to prevent respiratory distress syndrome.
  • Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. Niemann-Pick Disease (also known as sphingomyelin-cholesterol lipidosis): a group of autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorders characterized by the accumulation of sphingomyelin and cholesterol in cells, most notably neurons.
  • Essential fatty acid deficiency: linoleic and alpha-linolenic acid are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation. Symptoms include skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions and impairment of lipid transport. At-risk groups include infants receiving formula diets low in fat and patients maintained exclusively on intravenous nutrition for long periods of time.
  • Abnormal metabolism of essential fatty acids: can be related to dietary insufficiency, but can occur in multiple diseases. These include cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis, acrodermatitis enteropathica, hepatorenal syndrome Hepatorenal Syndrome Hepatorenal syndrome (HRS) is a potentially reversible cause of acute kidney injury that develops secondary to liver disease. The main cause of HRS is hypovolemia, often as a result of forced diuresis or drainage of ascites. This leads to renal vasoconstriction resulting in hypoperfusion of the kidneys. Hepatorenal Syndrome, Crohn disease, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, chronic alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder, and Reye syndrome.

References

  1. Botham, K. M., & Mayes, P. A. (2018). Lipids of physiologic significance. In V. W. Rodwell, et al. (Ed.). Harper’s illustrated biochemistry (31st ed.).
  2. Bender, D. A. (2018). Micronutrients: Vitamins & minerals. In V. W. Rodwell, et al. (Ed.). Harper’s illustrated biochemistry (31st ed.).
  3. Marchili, M. R., et al. (2018). Vitamin K deficiency: a case report and review of current guidelines. Italian journal of pediatrics, 44(1), 36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853086/
  4. Richardson, M., & Khosla, C. (1999). Comprehensive Natural Products Chemistry (Vol. 1). Comprehensive Natural Products Chemistry. Elsevier.
  5. Sommer, A. (2008). Vitamin a deficiency and clinical disease: A historical overview. The Journal of Nutrition, 138(10), 1835–1839. https://www.ncbi.nlm.nih.gov/pubmed/18806089

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