Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure

Liakath‐Ali, Kifayathullah; Vancollie, Valerie E.; Lelliott, Christopher J.; Speak, Anneliese O.; Lafont, David; Protheroe, Hayley; Ingvorsen, Camilla; Galli, Antonella; Green, Angela; Gleeson, Diane; Ryder, Edward; Glover, Leanne; Vizcay‐Barrena, Gema; Karp, Natasha A.; Arends, Mark J.; Brenn, Thomas; Spiegel, Sarah; Adams, David J.; Watt, Fiona M.; Weyden, Louise van der

doi:10.1002/path.4737

Cited by 35 publications

(36 citation statements)

References 27 publications

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“…Although the role of ACER1 (REF. 71) in cancer is currently unknown, activation of ACER2 increased cancer cell death in response to doxorubicin-induced DNA damage owing to sphingosine accumulation and reactive oxygen species signalling, despite a reduction in ceramide generation 72 . ACER3 selectively catabolizes C18:1 ceramides and C20:1 ceramides, which contain unsaturated forms of C18 and C20 fatty acids such as oleic acid or paullinic acid, respectively, whereas conventional C18 ceramide and C20 ceramide contain saturated fatty acids such as stearic acid or arachidic acid, respectively.…”

Section: Sphingolipid Metabolism and Cancermentioning

confidence: 99%

Sphingolipid metabolism in cancer signalling and therapy

2017

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Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

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Section: Sphingolipid Metabolism and Cancermentioning

confidence: 99%

Sphingolipid metabolism in cancer signalling and therapy

2017

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“…Alkaline ceramidase ACER1 has a mass of approximately 31 kDa and is 264 amino acids in length. It has been reported to be a membrane protein localized at the ER [36,37] with a catalytic pH optimum of 9.0 (Table 1) [38]. ACER1 is highly expressed in the differentiated interfollicular epidermis, sebaceous gland, and infundibulum.…”

Section: Alkaline Ceramidasesmentioning

confidence: 99%

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Parveen

Bender

Law

et al. 2019

Cells

102

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Human pathologies such as Alzheimer’s disease, type 2 diabetes-induced insulin resistance, cancer, and cardiovascular diseases have altered lipid homeostasis. Among these imbalanced lipids, the bioactive sphingolipids ceramide and sphingosine-1 phosphate (S1P) are pivotal in the pathophysiology of these diseases. Several enzymes within the sphingolipid pathway contribute to the homeostasis of ceramide and S1P. Ceramidase is key in the degradation of ceramide into sphingosine and free fatty acids. In humans, five different ceramidases are known—acid ceramidase, neutral ceramidase, and alkaline ceramidase 1, 2, and 3—which are encoded by five different genes (ASAH1, ASAH2, ACER1, ACER2, and ACER3, respectively). Notably, the neutral ceramidase N-acylsphingosine amidohydrolase 2 (ASAH2) shows considerable differences between humans and animals in terms of tissue expression levels. Besides, the subcellular localization of ASAH2 remains controversial. In this review, we sum up the results obtained for identifying gene divergence, structure, subcellular localization, and manipulating factors and address the role of ASAH2 along with other ceramidases in human diseases.

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“…It is essential for skin homeostasis and whole-body energy homeostasis (Liakath-Ali et al, 2016). Immunofluorescence studies with over expressed ACER1 showed that the protein is expressed in the endoplasmic reticulum.…”

Section: Alkaline Ceramidase 1 (Acer1)mentioning

confidence: 99%

Ceramidases, roles in sphingolipid metabolism and in health and disease

Coant

Sakamoto

Mao

et al. 2017

Advances in Biological Regulation

203

146

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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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Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole-body energy expenditure

Cited by 35 publications

References 27 publications

Sphingolipid metabolism in cancer signalling and therapy

Sphingolipid metabolism in cancer signalling and therapy

Role of Ceramidases in Sphingolipid Metabolism and Human Diseases

Ceramidases, roles in sphingolipid metabolism and in health and disease

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