Lipids, driven by their hydrophobic and hydrophilic portions, form the biological membranes found in all living creatures. These include the cell and nuclear membranes as well as membranes that are part of organelles such as mitochondria and the endoplasmic reticulum (ER). Membranes provide separation of different environments to permit a variety of biological functions. Membranes are not static structures, though, rather they are dynamic and fluid and allow selective movement of ions, energy sources, vitamins and cofactors, and waste. Complex lipids such as cholesterol and sphingolipids both affect the structure of membranes where they are found and are also involved in specific functions.

The variety of lipid and protein molecules, which make up membranes, are responsible for essential functions such as channels and transport across the membrane as well as signaling. Membrane receptors, along with their cytoplasmic partners, transmit signals via steroid hormones. An important type of membrane receptors are G-proteins with intrinsic enzyme activity. The resulting secondary messenger molecules amplify and transmit this signal to various parts of the cytoplasm and nucleus. This ability to transmit a message across a membrane is paramount to not only the normal functions of cells but also their ability to perform specialized functions, which define the human body.

Not surprisingly, lipids and membrane structure and function are important in disease processes as well as treatments. Any deficiencies or problems with lipid synthesis or breakdown lead to a serious disease state and/or death. Modulation of membrane fluidity is, itself, important in membrane functions and, as a result, a variety of diseases. For example, multiple bacteria and viruses are infective and several medications work simply because their hydrophobic nature affects and directly targets lipids and membranes.

Lipids

Membranes are composed of lipids arranged in a lipid bilayer, with the hydrophilic glycerol and phosphate “head” groups of the lipid molecules forming the two outside layers and the hydrophobic “tail” groups arranged inside (Figure 8-1).

A majority of membrane lipids are phospholipids, usually with 16- or 18-carbon tails, some saturated and some unsaturated. Other types of lipids, including cholesterol, modulate the structure and, therefore, the fluidity of the membrane and, in turn, affect some membrane functions.

Particular lipids are found in specific membranes and are responsible for specific function as summarized below:

• Cardiolipin (Diphosphatidylglycerol)—Several locations including the inner mitochondrial membrane. It has a negative charge and may be involved in (a) decreasing blood clots, (b) stabilizing important respiratory chain enzymes in the mitochondria, (c) moving proteins and cholesterol from the outer to the inner mitochondrial membrane, (d) assisting in the proper folding of mitochondrial proteins (Chapter 9) as a chaperone, and (e) possibly regulating deoxyribonucleic acid (DNA) synthesis.
  
• Phosphatidylserine (PS)—Located in the inner platelet membrane and, during activation, the exterior platelet membrane. It carries a negative charge and is the primary phospholipid that promotes the anticoagulant protein C pathway, providing feedback inhibition of thrombin formation.
  
• Phosphatidylethanolamine (PE)—Located in both the interior and exterior of cell membranes. It carries a neutral charge and promotes the anticoagulant protein C pathway, but to a lesser degree than PS.
  
• Phosphatidylcholine (PC)—Located in the interior and exterior of cell membranes. It carries a neutral charge and promotes the anticoagulant protein C pathway, but to a lesser degree than PS.
  
• Phosphatidylinositol—Located in the interior and exterior of cell membranes as well as the nuclear membrane. It carries a positive charge and promotes the anticoagulant protein C pathway, but to a lesser degree than PS, and is important in signaling processes for initiation of DNA replication.

The smaller head groups of phospholipids such as PS and PE are preferred on the inner side of the membrane bilayer. On the other hand, PS is often located on the outside of the bilayer where it can increase adherence to other cells and tissues. A membrane-bound enzyme called “flippase” catalyzes the process of moving particular phospholipid molecules from one side of the bilayer to the other when required. Other phospholipids, because of their head group size and charges as well as the number and location of their tail double bonds, create a more fluid membrane more amenable to areas of cell curvature or cell—cell connections (Figure 8-2).

Composition of the plasma membrane and, therefore, fluidity has been implicated in several disease processes, including the following:

1. 
   

   During stages of infection with malaria, the composition of infected red blood cells is markedly changed to mimic that of the infecting parasite. This may assist in the rupture of red blood cells and the subsequent spread of the parasites that is a hallmark of this disease.

   
   
2. 
   

   Various bacteria and viruses are believed to change the plasma membrane of target cells to allow the bacteria/virus to fuse and, therefore, infect the modified cells.

   
   
3. 
   

   Human immunodeficiency virus (HIV) fuses with specific parts of an infected cell’s membrane similar to its own viral membrane in composition and fluidity, allowing new viral particles to emerge and spread to other cells. Research has shown that changing membrane composition of target cells may allow protection from HIV infection.

   
   
4. 
   

   The parasite Entamoeba histolytica produces proteins that bind to and form holes in human cell membranes, killing these target cells. However, the parasite membrane has a markedly different membrane composition, including different phospholipids and a high level of cholesterol, which protects itself from these deadly proteins.

   
   
5. 
   

   Membrane composition is markedly changed in the platelets of patients with frequent migraines. Although the mechanism is not known, these changes may be part of the cause of migraine headaches and a better understanding could, therefore, lead to a novel treatment.

   
   
6. 
   

   Virgin olive oil alters the composition of plasma membranes and affects regulatory proteins in the lipid bilayer, which results in beneficial changes in carbohydrate and lipid metabolism.

The presence and amount of cholesterol also influence the fluidity of membranes. Cholesterol’s hydroxyl group readily interacts with phospholipid head groups or exterior water molecules and the remaining hydrophobic tetracyclic structure and “tail” also naturally insert inside the lipid bilayer (Figure 8-3). Hydrogen bonding stabilizes these interactions. Depending on the adjacent lipids, cholesterol either increases or decreases the lipid tail packing. Localized membrane “rafts” containing high levels of cholesterol have been noted by researchers and are felt to directly influence not only membrane functions but also the functions of the membrane proteins within them.

Proteins

Proteins are the second major part of biological membranes and make up approximately 20%–80% of both the structural and functional components of these membranes. Membrane proteins are classified as peripheral—predominately on the inner or the outer surface of the membrane bilayer—and integral—predominately within the membrane (Figure 8-4). Peripheral membrane proteins are believed to mainly act as anchor points for attachment to external structures (e.g., the extracellular matrix) and internal points (e.g., the actin, microtubule, and intermediate filament cytomatrix; Chapter 12). Integral proteins are usually composed of uncharged, hydrophobic amino acids so they can enter and stay in the hydrophobic environment of the lipid bilayer. Integral proteins serve several functions including channels, “carrier proteins” (transporting molecules through the membrane), or as a signaling protein (changing a portion of their internal cytoplasmic structure in response to a signal at an exposed external part of their structure to activate additional, closely associated molecules, leading to a change of function, e.g., turning on a gene).

As already illustrated, the membrane content of cholesterol and saturated/unsaturated lipids impacts membrane fluidity. Membrane proteins form connections to the extracellular matrix, the internal cytomatrix, and even other cells that can allow particular proteins and lipids to collect at special areas of a biological membrane. Thus, a cell can orchestrate a particular “area” or “side” where it can receive signals and/or transport particular molecules both in and out and/or other essential functions. These specialized “domains” within membranes are called “lipid rafts” (Figure 8-5). Various examples of these membrane protein functions are discussed below.