@article{GohlkeZagoriyInostrozaetal.2019, author = {Gohlke, Sabrina and Zagoriy, Vyacheslav and Inostroza, Alvaro Cuadros and Meret, Michael and Mancini, Carola and Japtok, Lukasz and Schumacher, Fabian and Kuhlow, Doreen and Graja, Antonia and Stephanowitz, Heike and J{\"a}hnert, Markus and Krause, Eberhard and Wernitz, Andreas and Petzke, Klaus-Juergen and Sch{\"u}rmann, Annette and Kleuser, Burkhard and Schulz, Tim Julius}, title = {Identification of functional lipid metabolism biomarkers of brown adipose tissue aging}, series = {Molecular Metabolism}, volume = {24}, journal = {Molecular Metabolism}, publisher = {Elsevier}, address = {Amsterdam}, issn = {2212-8778}, doi = {10.1016/j.molmet.2019.03.011}, pages = {1 -- 17}, year = {2019}, abstract = {Objective: Aging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism. Methods: Samples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined. Results: Corroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation. Conclusions: Our functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions.}, language = {en} } @article{NojimaFreemanSchusteretal.2016, author = {Nojima, Hiroyuki and Freeman, Christopher M. and Schuster, Rebecca M. and Japtok, Lukasz and Kleuser, Burkhard and Edwards, Michael J. and Gulbins, Erich and Lentsch, Alex B.}, title = {Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate}, series = {Journal of hepatology}, volume = {64}, journal = {Journal of hepatology}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0168-8278}, doi = {10.1016/j.jhep.2015.07.030}, pages = {60 -- 68}, year = {2016}, abstract = {Background \& Aims: Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury. Methods: Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo. Results: Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases. Conclusions: Our data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.}, language = {en} } @article{FayyazHenkelJaptoketal.2014, author = {Fayyaz, Susann and Henkel, Janin and Japtok, Lukasz and Kr{\"a}mer, Stephanie and Damm, Georg and Seehofer, Daniel and P{\"u}schel, Gerhard Paul and Kleuser, Burkhard}, title = {Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P(2) receptor subtype}, series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, volume = {57}, journal = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)}, number = {2}, publisher = {Springer}, address = {New York}, issn = {0012-186X}, doi = {10.1007/s00125-013-3123-6}, pages = {373 -- 382}, year = {2014}, abstract = {Enhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance. The incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice. Palmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P(2) receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P(2), was not able to inhibit insulin signalling. These data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P(2) receptor to impair insulin signalling. In particular, S1P(2) inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.}, language = {en} }