[9] Nussbaum et al add regulation of lipid droplets to this list

[9] Nussbaum et al. add regulation of lipid droplets to this list by reporting that low levels of H2O2 prevent steatosis in gmps mutants, and that antioxidant supplementation to wild-type larvae reduces homeostatic ROS and induces steatosis. Whether modulating homeostatic ROS in humans by antioxidant treatment affects steatosis has yet to be evaluated. How JNK inhibitor does disrupting the GMP-Rac1 axis contribute to lipid accumulation in hepatocytes? Tantalizing evidence of deregulation of lipid droplet hydrolysis

as a mechanism for steatosis is proposed by their finding that ces3 was downregulated in larvae deficient for the GMP synthesis-Rac1 axis. Moreover, simply treating larvae with a low dose of H2O2 restores ces3 expression in gmps mutants. This contrasts with a recent study using mice deficient for Ces3/Tgh, which had a marked

decrease in steatosis in both fasted and fed states. Pharmacologic inhibition of Tgh reduced lipid turnover in primary human hepatocytes,[10] suggesting that Ces3 reduction could alternatively reduce or increase lipid droplet formation in different contexts. It will be interesting to delineate whether Tgh/Ces3 regulation is a genuine and conserved factor that prevents steatosis across species. This work highlights a number of intriguing issues that may inform clinical practice. For instance, there are substantial data that support see more the use of antioxidants to reduce liver injury in FLD patients. However, it is possible that antioxidants also suppress the generation

of homeostatic levels of ROS, which may reduce tgh/ces3 expression and, as a consequence, prevent hydrolysis of lipid droplets, leading to steatosis. Also, given that GMP appears an important factor in regulating lipid droplet formation, it is exciting to speculate that supplementation of this nucleotide may serve to suppress this pathway in patients. Finally, this work provides an illustrative example of how using unbiased screening, and unconventional models, can generate surprising and novel ideas that advance our understanding of FLD and provide new areas to exploit for therapeutic intervention. learn more Orkhontuya Tsedensodnom, Ph.D.1,2Kirsten C. Sadler, Ph.D.1-3 “
“Previous studies demonstrated that targeted deletion of the Ron receptor tyrosine kinase (TK) domain in mice leads to marked hepatocyte protection in a well-characterized model of lipopolysaccharide (LPS)-induced acute liver failure in D-galactosamine (GalN)-sensitized mice. Hepatocyte protection in TK−/− mice was observed despite paradoxically elevated serum levels of tumor necrosis factor alpha (TNF-α). To understand the role of Ron in the liver, purified populations of Kupffer cells and hepatocytes from wildtype (TK+/+) and TK−/− mice were studied.

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