Chemistry and Biology of HPAs: A Family of Ceramide Trafficking Inhibitors

Berkeš, Dušan; Daı̈ch, Adam; Santos, Cécile; Ballereau, Stéphanie; Génisson, Yves

doi:10.1002/chem.201602947

Cited by 11 publications

(11 citation statements)

References 46 publications

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“…CERT obviously contributes to cell survival or cell death in more than one manner and a lowering of CERT expression can also provide advantages to tumor cells. This may also match with a recent study, which revealed a novel function of CERT and CERTL in the classical innate immune response, suggesting CERTL’s participation in apoptotic cell clearance [30]. CERT downregulation may be a way for the tumor cells to attenuate complement activation and thus evade the immune system.…”

Section: Ceramide Transfer Protein (Cert)supporting

confidence: 89%

“…It is structurally related to ceramide and shows potent cellular activity at concentrations between 0.1 to 2.5 µM (Figure 2). Since then, various syntheses and derivatives of HPA-12 have been published [30,32]. Very recently, the first not ceramide-related CERT inhibitor, HPCB-5, was identified by a virtual screening approach [33].…”

Section: Ceramide Transfer Protein (Cert)mentioning

confidence: 99%

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Sphingolipid-Transporting Proteins as Cancer Therapeutic Targets

Samaha

Hamdo

Wilde

et al. 2019

IJMS

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The understanding of the role of sphingolipid metabolism in cancer has tremendously increased in the past ten years. Many tumors are characterized by imbalances in sphingolipid metabolism. In many cases, disorders of sphingolipid metabolism are also likely to cause or at least promote cancer. In this review, sphingolipid transport proteins and the processes catalyzed by them are regarded as essential components of sphingolipid metabolism. There is much to suggest that these processes are often rate-limiting steps for metabolism of individual sphingolipid species and thus represent potential target structures for pharmaceutical anticancer research. Here, we summarize empirical and biochemical data on different proteins with key roles in sphingolipid transport and their potential role in cancer.

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Section: Ceramide Transfer Protein (Cert)supporting

confidence: 89%

Section: Ceramide Transfer Protein (Cert)mentioning

confidence: 99%

Sphingolipid-Transporting Proteins as Cancer Therapeutic Targets

Samaha

Hamdo

Wilde

et al. 2019

IJMS

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“…Most ceramides are then transported to the Golgi to be converted into glycosphingolipids and sphingomyelin. Ceramide transport protein (Cert) mediates ceramide transport for sphingomyelin biosynthesis, which can be inhibited by HPA-12 (Berkes et al, 2016; Duris et al, 2011; Hanada, 2014, 2017; Hanada et al, 2003; Kumagai et al, 2005; Santos et al, 2015). Conversion of ceramide to glucosylceramide is the first step in biosynthesis of raft-associated glycosphingolipids and it is catalyzed by glucosylceramide synthase, a Golgi resident enzyme inhibited by l-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or deoxynojirimycin-type compounds (Bieberich et al, 1999; Gu et al, 2017; Mellor et al, 2004).…”

Section: Detection Preparation and Visualization Of Rafts And Theirmentioning

confidence: 99%

Sphingolipids and lipid rafts: Novel concepts and methods of analysis

Bieberich

2018

Chemistry and Physics of Lipids

176

119

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About twenty years ago, the functional lipid raft model of the plasma membrane was published. It took into account decades of research showing that cellular membranes are not just homogenous mixtures of lipids and proteins. Lateral anisotropy leads to assembly of membrane domains with specific lipid and protein composition regulating vesicular traffic, cell polarity, and cell signaling pathways in a plethora of biological processes. However, what appeared to be a clearly defined entity of clustered raft lipids and proteins became increasingly fluid over the years, and many of the fundamental questions about biogenesis and structure of lipid rafts remained unanswered. Experimental obstacles in visualizing lipids and their interactions hampered progress in understanding just how big rafts are, where and when they are formed, and with which proteins raft lipids interact. In recent years, we have begun to answer some of these questions and sphingolipids may take center stage in re-defining the meaning and functional significance of lipid rafts. In addition to the archetypical cholesterol-sphingomyelin raft with liquid ordered (Lo) phase and the liquid-disordered (Ld) non-raft regions of cellular membranes, a third type of microdomains termed ceramide-rich platforms (CRPs) with gel-like structure has been identified. CRPs are “ceramide rafts” that may offer some fresh view on the membrane mesostructure and answer several critical questions for our understanding of lipid rafts.

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“…2B). We inhibited the activity of CERT in muscle cells by using the CERT inhibitor HPA12 (18). HPA12 inhibited CERT activity through its interaction with the stAR-related lipid-transfer domain of CERT that usually binds ceramides (30).…”

Section: Influence Of the Modulation Of Cert Activity/ Expression On mentioning

confidence: 99%

Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions

et al. 2018

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One main mechanism of insulin resistance (IR), a key feature of type 2 diabetes, is the accumulation of saturated fatty acids (FAs) in the muscles of obese patients with type 2 diabetes. Understanding the mechanism that underlies lipid-induced IR is an important challenge. Saturated FAs are metabolized into lipid derivatives called ceramides, and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi apparatus through a transporter called CERT, where they are converted into various sphingolipid species. We show that CERT protein expression is reduced in all IR models studied because of a caspase-dependent cleavage. Inhibiting CERT activity in vitro potentiates the deleterious action of lipotoxicity on insulin signaling, whereas overexpression of CERT in vitro or in vivo decreases muscle ceramide content and improves insulin signaling. In addition, inhibition of caspase activity prevents ceramide-induced insulin signaling defects in C2C12 muscle cells. Altogether, these results demonstrate the importance of physiological ER-to-Golgi ceramide traffic to preserve muscle cell insulin signaling and identify CERT as a major actor in this process.

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Chemistry and Biology of HPAs: A Family of Ceramide Trafficking Inhibitors

Cited by 11 publications

References 46 publications

Sphingolipid-Transporting Proteins as Cancer Therapeutic Targets

Sphingolipid-Transporting Proteins as Cancer Therapeutic Targets

Sphingolipids and lipid rafts: Novel concepts and methods of analysis

Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions

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