Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease

Over the past three decades, extensive research has been able to determine the biologic functions for the main bioactive sphingolipids, namely ceramide, sphingosine, and sphingosine 1-phosphate (S1P)(Hannun, 1996; Hannun et al., 1986; Okazaki et al., 1989). These studies have managed to define the metabolism, regulation, and function of these bioactive sphingolipids. This emerging body of literature has also implicated bioactive sphingolipids, particularly S1P and ceramide, as key regulators of cellular homeostasis. Ceramidases have the important role of cleaving fatty acid from ceramide and producing sphingosine, thereby controlling the interconversion of these two lipids. Thus far, five human ceramidases encoded by five different genes have been identified: acid ceramidase (AC), neutral ceramidase (NC), alkaline ceramidase 1 (ACER1), alkaline ceramidase 2 (ACER2), and alkaline ceramidase 3 (ACER3). These ceramidases are classified according to their optimal pH for catalytic activity. AC, which is localized to the lysosomal compartment, has been associated with Farber’s disease and is involved in the regulation of cell viability. Neutral ceramidase, which is localized to the plasma membrane and primarily expressed in the small intestine and colon, is involved in digestion, and has been implicated in colon carcinogenesis. ACER1 which can be found in the endoplasmic reticulum and is highly expressed in the skin, plays an important role in keratinocyte differentiation. ACER2, localized to the Golgi complex and highly expressed in the placenta, is involved in programed cell death in response to DNA damage. ACER3, also localized to the endoplasmic reticulum and the Golgi complex, is ubiquitously expressed, and is involved in motor coordination-associated Purkinje cell degeneration. This review seeks to consolidate the current knowledge regarding these key cellular players..

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“…This in turn resulted in S1P elevation. These results suggest that NC may protect against inflammation (Snider et al, 2012). …”

Section: Neutral Ceramidase (Asah2 Asah2b Asah2c)mentioning

confidence: 84%

Ceramidases, roles in sphingolipid metabolism and in health and disease

Coant

Sakamoto

Mao

et al. 2017

Advances in Biological Regulation

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195

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“…Additionally, the role of ceramidases in UC has recently been investigated. These studies, however, have found that despite the expression of neutral CDase and alkaline CDase 3 in the intestinal mucosa, these enzymes do not contribute to S1P-mediated inflammation and actually may have a protective role in UC (Fig 1) (Snider et al, 2012; Wang et al, 2016). Thus it remains inconclusive which sphingolipid enzymes and metabolites function in connection to drive particular mechanistic signatures of inflammation in UC.…”

Section: Bioactive Sphingolipid Signaling In Ulcerative Colitismentioning

confidence: 94%

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

Espaillat

Kew

Obeid

2017

Advances in Biological Regulation

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Bioactive sphingolipids are regulators of immune cell function and play critical roles in inflammatory conditions including ulcerative colitis. As one of the major forms of inflammatory bowel disease, ulcerative colitis pathophysiology is characterized by an aberrant intestinal inflammatory response that persists causing chronic inflammation and tissue injury. Innate immune cells play an integral role in normal intestinal homeostasis but their dysregulation is thought to contribute to the pathogenesis of ulcerative colitis. In particular, neutrophils are key effector cells and are first line defenders against invading pathogens. While the activity of neutrophils in the intestinal mucosa is required for homeostasis, regulatory mechanisms are equally important to prevent unnecessary activation. In ulcerative colitis, unregulated neutrophil inflammatory mechanisms promote tissue injury and loss of homeostasis. Aberrant neutrophil function represents an early checkpoint in the detrimental cycle of chronic intestinal inflammation; thus, dissecting the mechanisms by which these cells are regulated both before and during disease is essential for understanding the pathogenesis of ulcerative colitis. We present an analysis of the role of sphingolipids in the regulation of neutrophil function and the implication of this relationship in ulcerative colitis.

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“…Kono et al (2006) demonstrated that loss of nCDase activity impairs the intestinal degradation of ceramide, and suggests that nCDase is a key enzyme in the catabolism of dietary sphingolipids and regulates of the cellular levels of ceramide and sphingosine in the gastrointestinal tract. Additionally, Snider et al (2012) recently reported that, under inflammatory bowel disease conditions, loss of nCDase activity results in an unexpected increase in both S1P generation and inflammatory responses, and suggests that nCDase may play a protective role in regulating inflammation and S1P levels.…”

Section: Ceramidases and Their Role In Regulating Cellular Responsesmentioning

confidence: 99%

Inhibitors of Ceramidases

Saied

2016

Chemistry and Physics of Lipids

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Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease

Cited by 53 publications

References 41 publications

Ceramidases, roles in sphingolipid metabolism and in health and disease

Ceramidases, roles in sphingolipid metabolism and in health and disease

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

Inhibitors of Ceramidases

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