Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin

Holland, William L.; Miller, Russell A.; Wang, Zhao V.; Sun, Kai; Barth, Brian M.; Bui, Hai H.; Davis, Kathryn E.; Bikman, Benjamin T.; Halberg, Nils; Rutkowski, Joseph M.; Wade, Mark; Tenorio, Vincent M.; Kuo, Ming Shang; Brozinick, Joseph T.; Zhang, Bei B.; Birnbaum, Morris J.; Summers, Scott A.; Scherer, Philipp E.

doi:10.1038/nm.2277

Cited by 761 publications

(817 citation statements)

References 61 publications

Supporting

Mentioning

764

Contrasting

Unclassified

Order By: Relevance

“…Type 2 diabetes is characterized by peripheral insulin resistance, ␤-cell dysfunction, and loss of ␤-cell mass. Dysfunctional sphingolipid metabolism is known to cause peripheral insulin resistance (35)(36)(37). The present study now extends our understanding of the importance of sphingolipid metabolism in diabetes susceptibility by identifying Sgpp2 as a gene controlling adaptive ␤-cell mass expansion.…”

Section: Discussionsupporting

confidence: 59%

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

Taguchi¹,

Allende²,

Mizukami

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates basic cell functions through metabolic and signaling pathways. Intracellular metabolism of S1P is controlled, in part, by two homologous S1P phosphatases (SPPases), 1 and 2, which are encoded by the Sgpp1 and Sgpp2 genes, respectively. SPPase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. SPPase 1 is important for skin homeostasis, but little is known about the functional role of SPPase 2. To identify the functions of SPPase 2 in vivo, we studied mice with the Sgpp2 gene deleted. In contrast to Sgpp1 ؊/؊ mice, Sgpp2 ؊/؊ mice had normal skin and were viable into adulthood. Unexpectedly, WT mice expressed Sgpp2 mRNA at high levels in pancreatic islets when compared with other tissues. Sgpp2 ؊/؊ mice had normal pancreatic islet size; however, they exhibited defective adaptive ␤-cell proliferation that was demonstrated after treatment with either a high-fat diet or the ␤-cell-specific toxin, streptozotocin. Importantly, ␤-cells from untreated Sgpp2 ؊/؊ mice showed significantly increased expression of proteins characteristic of the endoplasmic reticulum stress response compared with ␤-cells from WT mice, indicating a basal islet defect. Our results show that Sgpp2 deletion causes ␤-cell endoplasmic reticulum stress, which is a known cause of ␤-cell dysfunction, and reveal a juncture in the sphingolipid recycling pathway that could impact the development of diabetes.Sphingosine 1-phosphate (S1P) 3 is a potent bioactive lipid produced from the degradation of plasma membrane sphingolipids (1-3). As a signaling molecule, S1P exerts effects in a variety of biological processes through interactions with both extracellular receptors and intracellular targets. As an intracellular metabolic intermediate, S1P is readily metabolized to other bioactive sphingolipids, such as ceramide and sphingosine, as well as to other lipids (Fig. 1A). S1P and its metabolites control basic cell functions, such as proliferation, apoptosis, and migration, and are involved in several pathologic conditions, including inflammation, metabolic disease, and cancer (1, 2). Thus, insight into S1P metabolism and how this regulates its functional activity is of key importance in understanding the role of S1P in biology and disease. S1P is produced by the sphingosine kinase-dependent phosphorylation of sphingosine, which is created as a degradation product of ceramide (4). Within cells, S1P is degraded through two pathways, either by irreversible cleavage by S1P lyase (5) or by dephosphorylation by specific S1P phosphatases (SPPases) (also known as S1P phosphohydrolases) (6). When cleaved by S1P lyase (Sgpl1), phosphoethanolamine and hexadecenal are produced, which are then transferred as substrates from the sphingolipid pathway to the glycerophospholipid pathway.In an alternative catabolic route catalyzed by S1P phosphatases, the resulting sphingosine product can be derivatized with a fatty acid by ceramide synthase to produce cer...

show abstract

Section: Discussionsupporting

confidence: 59%

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

Taguchi¹,

Allende²,

Mizukami

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The increase in sphingosine-1-phosphate is not without precedent as this has been observed in other cellular systems with short-chain ceramide analogs where it has explained seemingly similar observations with the use of short-chain ceramide analogs or sphingosine-1-phosphate. 32 In our study, we employed either gemcitabine or Lip-PDMP as means to improve the therapeutic efficacy of Lip-C 6 . As expected with an inhibitor of glucosylceramide synthase, the use of Lip-PDMP in combination with Lip-C 6 yielded a near-complete loss in the conversion of C 6 -ceramide to C 6 -cerebroside with a concomitant increase in the amount of C 6 -ceramide in PANC-1 cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer

Jiang

DiVittore

Kaiser

et al. 2011

Cancer Biology & Therapy

View full text Add to dashboard Cite

“…This isoform affects PPARα activity, which regulates lipid metabolism through gene transcription and increased expression of its ligands [54]. Adiponectin receptors also have ceramidase stimulatory activity, which lowers intracellular ceramide, increases sphingosine 1-phosphate levels, and protects against apoptosis [55].…”

Section: Adiponectinmentioning

confidence: 99%

Adipose tissue, obesity and adipokines: role in cancer promotion

Booth

Magnuson

Fouts

et al. 2015

Hormone Molecular Biology and Clinical Investigation

208

211

View full text Add to dashboard Cite

Adipose tissue is a complex organ with endocrine, metabolic and immune regulatory roles. Adipose depots have been characterized to release several adipocytokines that work locally in an autocrine and paracrine fashion or peripherally in an endocrine fashion. Adipocyte hypertrophy and excessive adipose tissue accumulation, as occurs during obesity, dysregulates the microenvironment within adipose depots and systemically alters peripheral tissue metabolism. The term "adiposopathy" is used to describe this promotion of pathogenic adipocytes and associated adipose -elated disorders. Numerous epidemiological studies confirm an association between obesity and various cancer forms. Proposed mechanisms that link obesity/adiposity to high cancer risk and mortality include, but are not limited to, obesity-related insulin resistance, hyperinsulinemia, sustained hyperglycemia, glucose intolerance, oxidative stress, inflammation and/or adipocktokine production. Several epidemiological studies have demonstrated a relationship between specific circulating adipocytokines and cancer risk. The aim of this review is to define the function, in normal weight and obesity states, of wellcharacterized and novel adipokines including leptin, adiponectin, apelin, visfatin, resistin, chemerin, omentin, nesfatin and vaspin and summarize the data that relates their dysfunction, whether associated or direct effects, to specific cancer outcomes. Overall research suggests most adipokines promote cancer cell progression via enhancement of cell proliferation and migration, inflammation and anti-apoptosis pathways, which subsequently can prompt cancer metastasis. Further research and longitudinal studies are needed to define the specific independent and additive roles of adipokines in cancer progression and reoccurrence.

show abstract

Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin

Cited by 761 publications

References 61 publications

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

Combinatorial therapies improve the therapeutic efficacy of nanoliposomal ceramide for pancreatic cancer

Adipose tissue, obesity and adipokines: role in cancer promotion

Contact Info

Product

Resources

About