Endogenous Synthesis Pathway Research Articles

Traceless synthesis of ceramides in living cells reveals saturation-dependent apoptotic effects

Mammalian cells synthesize thousands of distinct lipids, yet the function of many of these lipid species is unknown. Ceramides, a class of sphingolipid, are implicated in several cell-signaling pathways but poor cell permeability and lack of selectivity in endogenous synthesis pathways have hampered direct study of their effects. Here we report a strategy that overcomes the inherent biological limitations of ceramide delivery by chemoselectively ligating lipid precursors in vivo to yield natural ceramides in a traceless manner. Using this method, we uncovered the apoptotic effects of several ceramide species and observed differences in their apoptotic activity based on acyl-chain saturation. Additionally, we demonstrate spatiotemporally controlled ceramide synthesis in live cells through photoinitiated lipid ligation. Our in situ lipid ligation approach addresses the long-standing problem of lipid-specific delivery and enables the direct study of unique ceramide species in live cells.

Role of Hydrogen Sulfide in Retinal Diseases.

As the third gasotransmitter, hydrogen sulfide (H2S) plays a crucial role in the physiology and pathophysiology of many systems in the body, such as the nervous, cardiovascular, respiratory, and gastrointestinal systems. The mechanisms for its effects, including inhibiting ischemic injury, reducing oxidative stress damage, regulating apoptosis, and reducing the inflammation reaction in different systems, have not been fully understood. Recently, H2S and its endogenous synthesis pathway were found in the mammalian retina. This review describes the production and the metabolism of H2S and the evidence of a role of H2S in the retina physiology and in the different retinal diseases, including retinal degenerative diseases and vascular diseases. In the retina, H2S is generated in the presence of cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase from L-cysteine. The role of endogenous H2S and its physiologic effect in the retina are still elusive. However, strong evidence shows that retina-derived H2S might play protective or deleterious role in the pathogenesis of retinal diseases. For example, by regulating Ca2+ influx, H2S can protect retinal neurons against light-induced degeneration. H2S preconditioning can mediate the anti-apoptotic effect of retinal ganglion cells in retinal ischemia/reperfusion injury. Treatment with H2S in rats relieves diabetic retinopathy by suppressing oxidative stress and reducing inflammation. Further studies would greatly improve our understanding of the pathophysiologic mechanisms responsible for retinal diseases and the potential for the H2S-related therapy of the retinal diseases as well.

Cholesterol induces lipoprotein lipase expression in a tree shrew (Tupaia belangeri chinensis) model of non-alcoholic fatty liver disease.

Animal models are indispensible to investigate the pathogenesis and treatments of non-alcoholic fatty liver diseases (NAFLD). Altered cholesterol metabolism has been implicated into the pathogenesis of NAFLD. Here, using high fat, cholesterol and cholate diet (HFHC), we generated a novel tree shrew (Tupaia belangeri chinensis) model of NAFLD, which displayed dyslipidemia with increased levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-c) and high density lipoprotein-cholesterol (HDL-c), but decreased level of triglycerides (TG). Liver histopathology and genes expression indicated that HFHC diet successfully induced liver steatosis to inflammation and fibrosis progressively within 10 weeks. Moreover, HFHC induced the transcriptional expression of lipoprotein lipase (lpl) in the liver, but repressed the expression of LDL receptor, and the endogenous synthesis pathway and excretion of cholesterol. Notably, Poloxamer 407 (P-407) inhibition of LPL improved the severity of steatosis and reduced inflammation. These results illustrated that LPL plays an important role in cholesterol metabolism in NAFLD, and the tree shrew may be a valuable animal model for further research into NAFLD.