There are three major pathways involved in lipid signaling (see figure below). Ceramide has emerged as a potentially important pleiotropic signal transducer in apoptosis as well as in cell proliferation and differentiation. Ceramide is generated from sphingomyelin by the action of sphingomyelinase. All sphingolipids contain ceramide as the basic hydrophilic component that is released by activated sphingomyelinase. Sphingomyelinase can be activated by a variety of extracellular signals including tumor necrosis factor-a (TNF-a), g-interferon (g-IFN), interleukin-1 (IL-1), and ionizing radiation. The development of exogenous cell-permeable analogs of ceramide has facilitated the understanding of the intracellular effects of ceramide. Ceramide is reported to play an important role in the activation of NF-kB, protein kinase Cz, phospholipase A₂ (PLA₂), JNK/SAPK, and p42 MAP kinase. Recently, a ceramide-activated protein phosphatase (CAPP), belonging to the PP2A serine/threonine phosphatase family, has been reported and linked directly to the role of ceramide in apoptosis. Ceramide is also involved in the action of another major pathway in lipid signaling - the synthesis of eicosanoids via the activation of cyclooxygenase (also known as COX or prostaglandin endoperoxidase H synthase) and PLA₂.

An Overview of the Role of Bioactive Lipids in Signal Transduction

Activation of PLA₂ and generation of arachidonic acid is a major step in the downstream synthesis of prostaglandins, thromboxanes, and leukotrienes. PLA₂ is found in a wide variety of cells and its expression is stimulated by the action of a number of extracellular signals including TNF-a, IL-2, IL-6, and several inflammatory signals. The secreted PLA₂ requires millimolar levels of calcium for its activation. The activated PLA₂ then translocates to the membrane where it hydrolyzes glycerophospholipids at the sn2 position yielding free fatty acid (arachidonic acid) and lysophospholipid. The latter can yield platelet activating factor (PAF), another important second messenger, by the action of an acetyltransferase. Arachidonic acid undergoes a stepwise catalysis to yield reactive intermediates, PGG₂ and PGH₂, that serve as precursors of prostaglandins, prostacyclins, and thromboxanes. Prostaglandin, the 20-carbon polyunsaturated molecule generated by the action of prostaglandin endoperoxidase H synthase (PGHS), functions in an autocrine or paracrine manner. Prostaglandin action is mediated by a series of G-protein coupled cell surface receptors. PGHS, a tightly regulated enzyme, can exist as either PGHS-1 or PGHS-2. PGHS-1 is a constitutive enzyme and is associated with the endoplasmic reticulum. It is responsible for maintaining normal physiological functions and is considered as a “housekeeping” enzyme. On the other hand, PGHS-2 is an inducible enzyme that is mainly associated with the nuclear envelope. Its activity is induced by the action of several growth factors, cytokines, and inflammatory signals. More recently, free radical-catalyzed peroxidation of arachidonic acid is reported to lead to the generation of prostaglandin-like compounds known as isoprotanes (IsoPs). They are chemically stable products, formed in cellular membranes and subsequently released and excreted in the urine. Their discovery has opened up new areas of investigation regarding the role of free radicals in human physiology and pathophysiology. IsoPs have also been used as markers of oxidative stress in the pathogenesis of human disease. Higher levels of 8-iso- PGF2, one of the prominent IsoPs that acts as a vasoconstrictor, have been reported in atherosclerotic plaques and from brain tissue of Alzheimer’s patients.

More recently, there has been an upsurge of interest in COX-2 inhibitors as possible candidates for the treatment of Alzheimer’s disease. This is due to the fact that researchers have begun to think about “inflammation as a factor” in the development and/or progression of Alzheimer’s disease. Since neuronal excitation and oxidative stress have been linked to the pathogenesis of several neurodegenerative disorders, inhibiting excessive COX-2 activity may reduce the oxidative stress-induced neuronal damage and trauma. Several epidemiological studies have indeed shown that groups of people on nonsteroidal anti-inflammatory drugs (NSAIDs), for unrelated conditions, such conditions as rheumatoid arthritis, have a reduced incidence of Alzheimer’s disease. NSAIDs are believed to inhibit human Ab aggregation in vitro and reverse the b-sheet conformation of preformed fibrils

The third major pathway in lipid-signaling involves phosphoinositidespecific phospholipase C (PLC) that generates two ubiquitous second messengers—diacyglycerol (DAG) and inositol trisphosphate (IP₃). PLC is reported to exist in three major forms—b, g, and d. The PLCg is activated by tyrosine kinases, while the PLCb is regulated by the a-subunit of the Gq family of G-proteins as well as through the bg-subunits of the pertussis toxin-sensitive G-protein. Binding of a hormone or other effector molecule to the membrane receptor results in the activation of PLC via a G-protein-dependent phenomenon. The activated PLC hydrolyzes phosphatidylinositol- 4,5-bisphosphate (PIP₂) to produce DAG and IP₃. The IP₃ binds to the IP₃ receptor on the endoplasmic reticulum and causes the release of endogenous Ca²⁺ that binds to the cytosolic PKC and exposes the phospholipid binding site. The regulatory domain of PKC contains a Ca²⁺ binding site, designated the C2 region that is found only on a, b, and g-isozymes. The PKC isozymes d, e, h, q, m, and z lack the C2 region and do not require Ca²⁺ for their activation. The binding of Ca²⁺ translocates PKC to the membrane where it interacts with DAG to transform into a fully active enzyme. All PKC isoenzymes, with the exception of z and l, are activated by diacylglycerol (DAG) that acts by increasing the affinity of PKC for Ca²⁺ and helps in full activation of PKC without a net increase in Ca²⁺ concentration.