@article{NaserKadowSchumacheretal.2021,
  author    = {Naser, Eyad and Kadow, Stephanie and Schumacher, Fabian and Mohamed, Zainelabdeen H. and Kappe, Christian and Hessler, Gabriele and Pollmeier, Barbara and Kleuser, Burkhard and Arenz, Christoph and Becker, Katrin Anne and Gulbins, Erich and Carpinteiro, Alexander},
  title     = {Characterization of the small molecule ARC39},
  series = {Journal of Lipid Research},
  volume    = {61},
  journal   = {Journal of Lipid Research},
  number    = {6},
  publisher = {American Society for Biochemistry and Molecular Biology},
  address   = {Bethesda},
  issn      = {1539-7262},
  doi       = {10.1194/jlr.RA120000682},
  pages     = {896 -- 910},
  year      = {2021},
  abstract  = {Inhibition of acid sphingomyelinase (ASM), a lysosomal enzyme that catalyzes the hydrolysis of sphingomyelin into ceramide and phosphorylcholine, may serve as an investigational tool or a therapeutic intervention to control many diseases. Specific ASM inhibitors are currently not sufficiently characterized. Here, we found that 1-aminodecylidene bis-phosphonic acid (ARC39) specifically and efficiently (>90\%) inhibits both lysosomal and secretory ASM in vitro. Results from investigating sphingomyelin phosphodiesterase 1 (SMPD1/Smpd1) mRNA and ASM protein levels suggested that ARC39 directly inhibits ASM's catalytic activity in cultured cells, a mechanism that differs from that of functional inhibitors of ASM. We further provide evidence that ARC39 dose- and time-dependently inhibits lysosomal ASM in intact cells, and we show that ARC39 also reduces platelet- and ASM-promoted adhesion of tumor cells. The observed toxicity of ARC39 is low at concentrations relevant for ASM inhibition in vitro, and it does not strongly alter the lysosomal compartment or induce phospholipidosis in vitro. When applied intraperitoneally in vivo, even subtoxic high doses administered short-term induced sphingomyelin accumulation only locally in the peritoneal lavage without significant accumulation in plasma, liver, spleen, or brain. These findings require further investigation with other possible chemical modifications. In conclusion, our results indicate that ARC39 potently and selectively inhibits ASM in vitro and highlight the need for developing compounds that can reach tissue concentrations sufficient for ASM inhibition in vivo.},
  language  = {en}
}
@article{GohlkeManciniGarciaCarrizoetal.2021,
  author    = {Gohlke, Sabrina and Mancini, Carola and Garcia-Carrizo, Francisco and Schulz, Tim J.},
  title     = {Loss of the ciliary gene Bbs4 results in defective thermogenesis due to metabolic inefficiency and impaired lipid metabolism},
  series = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  volume    = {35},
  journal   = {The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology},
  number    = {11},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {1530-6860},
  doi       = {10.1096/fj.202100772RR},
  pages     = {13},
  year      = {2021},
  abstract  = {Adipose tissue is central to the regulation of energy balance. While white adipose tissue (WAT) is responsible for triglyceride storage, brown adipose tissue specializes in energy expenditure. Deterioration of brown adipocyte function contributes to the development of metabolic complications like obesity and diabetes. These disorders are also leading symptoms of the Bardet-Biedl syndrome (BBS), a hereditary disorder in humans which is caused by dysfunctions of the primary cilium and which therefore belongs to the group of ciliopathies. The cilium is a hair-like organelle involved in cellular signal transduction. The BBSome, a supercomplex of several Bbs gene products, localizes to the basal body of cilia and is thought to be involved in protein sorting to and from the ciliary membrane. The effects of a functional BBSome on energy metabolism and lipid mobilization in brown and white adipocytes were tested in whole-body Bbs4 knockout mice that were subjected to metabolic challenges. Chronic cold exposure reveals cold-intolerance of knockout mice but also ameliorates the markers of metabolic pathology detected in knockouts prior to cold. Hepatic triglyceride content is markedly reduced in knockout mice while circulating lipids are elevated, altogether suggesting that defective lipid metabolism in adipose tissue creates increased demand for systemic lipid mobilization to meet energetic demands of reduced body temperatures. These findings taken together suggest that Bbs4 is essential for the regulation of adipose tissue lipid metabolism, representing a potential target to treat metabolic disorders.},
  language  = {en}
}