ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier

Kien, Benedikt; Grond, Susanne; Haemmerle, Guenter; Lass, Achim; Eichmann, Thomas O.; Radner, Franz P.W.

doi:10.1194/jlr.m089771

Cited by 40 publications

(37 citation statements)

References 41 publications

(59 reference statements)

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“…5B). Recent studies (35,36) reported that CGI-58 recruits PNPLA1 to LDs, raising the possibility that CGI-58 promotes the activity of multiple PNPLA family members by stabilizing their interactions with LDs and access to lipid substrates. This possibility is consistent with Lord et al, (37) who showed that CGI-58 activates lipolysis independently of ATGL.…”

Section: Discussionmentioning

confidence: 99%

PNPLA3, CGI‐58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice

et al. 2019

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A variant (148M) in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) is a major risk factor for fatty liver disease. Despite its clinical importance, the pathogenic mechanism linking the variant to liver disease remains poorly defined. Previously, we showed that PNPLA3(148M) accumulates to high levels on hepatic lipid droplets (LDs). Here we examined the effect of that accumulation on triglyceride (TG) hydrolysis by adipose triglyceride lipase (ATGL), the major lipase in the liver. As expected, overexpression of ATGL in cultured hepatoma (HuH‐7) cells depleted the cells of LDs, but unexpectedly, co‐expression of PNPLA3(wild type [WT] or 148M) with ATGL inhibited that depletion. The inhibitory effect of PNPLA3 was not caused by the displacement of ATGL from LDs. We tested the hypothesis that PNPLA3 interferes with ATGL activity by interacting with its cofactor, comparative gene identification‐58 (CGI‐58). Evidence supporting such an interaction came from two findings. First, co‐expression of PNPLA3 and CGI‐58 resulted in LD depletion in cultured cells, but expression of PNPLA3 alone did not. Second, PNPLA3 failed to localize to hepatic LDs in liver‐specific Cgi ‐ 58 knockout (KO) mice. Moreover, overexpression of PNPLA3(148M) increased hepatic TG levels in WT, but not in Cgi ‐ 58 KO mice. Thus, the pro‐steatotic effects of PNPLA3 required the presence of CGI‐58. Co‐immunoprecipitation and pulldown experiments in livers of mice and in vitro using purified proteins provided evidence that PNPLA3 and CGI‐58 can interact directly. Conclusion: Taken together, these findings are consistent with a model in which PNPLA3(148M) promotes steatosis by CGI‐58‐dependent inhibition of ATGL on LDs.

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Section: Discussionmentioning

confidence: 99%

PNPLA3, CGI‐58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice

et al. 2019

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“…In contrast to systemic or epidermis-specific CGI-58 gene deletion, systemic ATGL knockout mice do not develop a defective skin permeability barrier despite epidermal TG accumulation suggesting an ATGL-independent function of CGI-58 in the skin [ 212 , 213 ]. In fact, very recently CGI-58 has been shown to stimulate ω-O-acylceramide synthesis in the skin that depends on protein interaction with PNPLA1, a close homologue of ATGL [ 214 ]. The role of PNPLA1 in ω-O-acylceramide synthesis and skin barrier function is discussed in detail within this Special Issue by Hirabayashi et al [ 215 ].…”

Section: What We Have Learnt From Mouse Models and Patientsmentioning

confidence: 99%

Of mice and men: The physiological role of adipose triglyceride lipase (ATGL)

Schreiber

Xie

Schweiger

2019

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

122

106

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Adipose triglyceride lipase (ATGL) has been discovered 14 years ago and revised our view on intracellular triglyceride (TG) mobilization – a process termed lipolysis. ATGL initiates the hydrolysis of TGs to release fatty acids (FAs) that are crucial energy substrates, precursors for the synthesis of membrane lipids, and ligands of nuclear receptors. Thus, ATGL is a key enzyme in whole-body energy homeostasis. In this review, we give an update on how ATGL is regulated on the transcriptional and post-transcriptional level and how this affects the enzymes' activity in the context of neutral lipid catabolism. In depth, we highlight and discuss the numerous physiological functions of ATGL in lipid and energy metabolism. Over more than a decade, different genetic mouse models lacking or overexpressing ATGL in a cell- or tissue-specific manner have been generated and characterized. Moreover, pharmacological studies became available due to the development of a specific murine ATGL inhibitor (Atglistatin®). The identification of patients with mutations in the human gene encoding ATGL and their disease spectrum has underpinned the importance of ATGL in humans. Together, mouse models and human data have advanced our understanding of the physiological role of ATGL in lipid and energy metabolism in adipose and non-adipose tissues, and of the pathophysiological consequences of ATGL dysfunction in mice and men.

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“…α/β hydrolase domain-containing protein 5 (ABHD5) has been identified to interact with PNPLA1 as a coactivator. It could be easily inferred that ABHD5 mutations can decrease epidermal ω-О-acylceramide synthesis, thereby causing ichthyosis [85]. Comparative gene identification-58 (CGI58) deficiency also impairs ω-О-acylceramide synthesis with severe barrier defects in Cgi58-deficient mice [86].…”

Section: Skin Lipidsmentioning

confidence: 99%

Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

Lee

2020

IJMS

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Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier.may not be the primary events in lesional skin. However, they can play a role in part as primary abnormalities because abnormalities in the epidermal barrier are already present in non-lesional skin of atopic dermatitis [1]. Epidermal trauma from tape stripping or irritant application also leads to initial disruption of the barrier, although the result at certain time points may be combined with compensatory reactions followed by trauma.Causative mechanisms involved in primary epidermal barrier dysfunction might be more valuable for the prevention of skin diseases induced by barrier abnormalities. However, the underlying mechanism has been discussed mainly in connection with immunologic responses, including cytokine production [1,9,10]. Accordingly, this review covers molecular mechanisms of epidermal barrier dysfunction as primary abnormalities by focusing on the causative factors of skin diseases (atopic dermatitis and ichthyoses) and experimental skin conditions (tape stripping and irritant application) associated with skin barrier abnormalities. Molecular Mechanisms Related to Epidermal Barrier DysfunctionFormation and maintenance of skin barrier integrity could be influenced by genetic and environmental factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Mechanisms related to epidermal barrier dysfunction at molecular levels have commonly illustrated filaggrin mutations [3,11]. Regarding the mechanism behind skin barrier integrity, the role of epidermal calcium gradients could be considered based on their influence on keratinocyte proliferation and dif...

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ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier

Cited by 40 publications

References 41 publications

PNPLA3, CGI‐58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice

PNPLA3, CGI‐58, and Inhibition of Hepatic Triglyceride Hydrolysis in Mice

Of mice and men: The physiological role of adipose triglyceride lipase (ATGL)

Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

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