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An unbiased approach de-livers unexpected insight into torsin biology
Sarah M. Prophet, Christian Schlieker
Sarah M. Prophet, Christian Schlieker
Published October 7, 2019
Citation Information: J Clin Invest. 2019;129(11):4576-4579. https://doi.org/10.1172/JCI132442.
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Commentary

An unbiased approach de-livers unexpected insight into torsin biology

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Abstract

Mutations affecting the integrity of the essential torsin ATPase/cofactor system have been identified in a steadily increasing number of congenital disorders. Since most of these mutations affect brain function, much of the research has focused on deciphering disease etiology in the brain. However, torsin is expressed in a wide variety of nonneural tissues and is strictly conserved across species, including the lowest metazoans, suggesting that it plays roles extending beyond neurons. In this issue of the JCI, Shin et al. explored torsin function in the mammalian liver. The group reports major defects in hepatic lipid metabolism when the torsin system is compromised in mice. Remarkably, conditional deletion of either torsinA or its cofactor, lamina-associated polypeptide 1 (LAP1), resulted in fatty liver disease and steatohepatitis, likely from a secretion defect of VLDLs. This study considerably expands our understanding of torsin biology, while providing defined opportunities for future investigations of torsin function and dysfunction in human pathologies.

Authors

Sarah M. Prophet, Christian Schlieker

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Figure 1

Possible roles for torsinA in the context of VLDL metabolism.

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Possible roles for torsinA in the context of VLDL metabolism.
(A) As WT ...
(A) As WT livers secrete VLDLs, the VLDLs are released into the bloodstream and processed into smaller lipoproteins to deliver lipids to peripheral tissue. A-CKO and L-CKO livers retain lipids (steatosis) as a result of compromised VLDL secretion and can become whitish and enlarged. (B) Models for torsinA involvement in VLDL biogenesis. While apoB100 is translated into the ER, MTP aids in apoB100 lipidation by extracting phospholipids (PLs) and TGs from the ER. In the absence of lipidation, apoB100 is degraded. TorsinA may facilitate unlipidated apoB100 degradation or cooperate with MTP to facilitate apoB100 lipidation. Alternatively, torsinA may be involved in coordinating the translocation, folding, and lipidation of apoB100. Once the VLDL precursor grows to an appropriate size within the ER, the mature VLDL travels to the Golgi. VLDLs are packaged into specialized vesicles that may require torsinA for their formation.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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