Glycerolipid, sphingolipid and sterol cell signaling pathways can cover major lipid metabolism signaling transduction, the misregulation of which may play a pivotal role in human disease.
Recent studies suggest that cellular stores of Triacylglyce (TAG) in lipid droplets release Fatty acids (FAs) that are channeled selectively to β-oxidation and that act as signals to influence the transcriptional control of gene expression. Additional studies suggest that the process of synthesizing or degrading TAG produces lipid intermediates like lysophosphatidic acid (LPA), phosphatidic acid (PA), and diacylglycerol (DAG) that may serve as activators or inhibitors of signaling pathways controlled by peroxisome proliferator-activated receptor-γ (PPARγ), the mammalian target of rapamycin (mTOR), or protein kinase C (PKC) isoforms. These signaling pathways may link excess intracellular TAG storage with insulin resistance.
Both the synthetic and the degradative pathways of Triacylglycerol (TAG) metabolism produce lipid molecules that are known to initiate signaling pathways when released from phospholipids: phospholipase A produces lysophosphatidic acid (LPA), phospholipase C produces diacylglycerol (DAG), and phospholipase D produces phosphatidic acid (PA).
LPA is a ligand for at least eight different G-protein coupled cell-surface receptors and may also activate PPARγ. Intracellular LPA may also activate LPA1 receptors on nuclear membranes to stimulate proinflammatory gene expression. PA, predominantly derived as a product of phospholipase D action on the plasma and mitochondrial membranes, also initiates intracellular signaling pathways, including those of mTOR, Raf-1, and others, but it has not been established whether the PA synthesized by AGPAT can do this. GPAT3 (LPAAT-Θ) overexpression in HEK293T cells increases phosphorylation of the mTOR target S6 kinase on Thr389 and eukaryotic translation initiation factor 4E-binding protein 1 on Ser65, suggesting that LPA or PA produced by the TAG synthetic pathway might activate mTOR.
Unlike other enzymes involved in TAG catabolism, MGL has been studied more for its role in cell signaling that its function as a lipolytic enzyme. This emphasis has arisen because MGL catalyzes the breakdown of sn-2-20:4-glycerol (2-AG), a member of the endocannabinoid family. Endocannabinoids signal through receptors to affect a wide range of physiological processes, including energy metabolism, inflammation, food intake, and behavior. By promoting the degradation of 2-AG and subsequently attenuating receptor binding, MGL may play a critical role in endocannabinoid signaling.
The major focus of this discussion of the sphingolipid metabolic pathways will be to explain how the different subspecies are produced. This begins with how the sphingoid bases arise since, by definition, all sphingolipids are comprised of that backbone. Most organisms derive a significant portion of their sphingoid bases from de novo biosynthesis because the first enzyme of the pathway (serine palmitoyltranserase) is essential for survival of cells in culture, from yeast to mammals, unless exogenous sphingoid bases are provided, and elimination of this enzyme is embryonic lethal for animals large (i.e., mammals) and small (e.g., fruit flies).
In the case of cholesterol biosynthesis from lanosterol, two intersecting routes have been postulated. The choice of pathway is determined by the stage at which the double bond at C24 in the sterol side chain is reduced. If C24 double bond reduction is retained until the last reaction, cholesterol synthesis proceeds via cholesta-5,24-dienol (desmosterol) (Bloch pathway). On the other hand, early Δ24-reduction involving lanosterol can proceed to cholesta-5,7-dienol (7-dehydrocholesterol) and cholesterol (KandutschRussell pathway). A common interpretation regarding which pathway is utilized involves the positioning of the Δ24-reductase in cholesterol biosynthesis such that skin and intestines, which have higher sterol C24-reductase activities than liver or brain, proceed via the C24 C25-terminal intermediates.10bd Regardless of tissue specificity, the kinetically favored pathway for cholesterol biosynthesis appears to involve the KandutschRussell pathway.
The relevant committed step that distinguishes sterol from isoprenoidtriterpenoid biosynthesis occurs at the cyclization of oxidosqualene. Major control points in sterol biosynthesis may arise in the primary pathway before squalene formation at hydroxymethyl-glutaryl-CoA reductase (HMGR) (coarse control) or after squalene formation at the sterol C24-methyltransferase (24-SMT) step (fine control) specific to organisms other than animals. Cofactor control by differential allocation of oxygen, NADPH, and AdoMet can further influence reaction rates and product distributions in cholesterol or phytosterol biosynthesis.
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