Abstract
Neutral lipid storage disease with myopathy (NLSDM) and with ichthyosis (NLSDI) are rare autosomal recessive disorders caused by mutations in the PNPLA2 and in the ABHD5/CGI58 genes, respectively. These genes encode the adipose triglyceride lipase (ATGL) and α-β hydrolase domain 5 (ABHD5) proteins, which play key roles in the function of lipid droplets (LDs). LDs, the main cellular storage sites of triacylglycerols and sterol esters, are highly dynamic organelles. Indeed, LDs are critical for both lipid metabolism and energy homeostasis. Partial or total PNPLA2 or ABHD5/CGI58 knockdown is characteristic of the cells of NLSD patients; thus, these cells are natural models with which one can unravel LD function. In this review we firstly summarize genetic and clinical data collected from NLSD patients, focusing particularly on muscle, skin, heart, and liver damage due to impaired LD function. Then, we discuss how NLSD cells were used to investigate and expand the current structural and functional knowledge of LDs.
Highlights
The human body stores excess amounts of biochemical energy in the form of triacylglycerols (TAGs).Together with cholesteryl esters (CEs), TAGs represent the vast majority of neutral lipids that are deposited in cytoplasmic inclusions known as lipid droplets (LDs) [1]
High incidence of mutation leads to a frameshift that produces a premature termination of translation and the formation of a truncated protein lacking 150 amino acids in the C-terminal region (p.R199Qfs*10). This mutation is present in 28% of NLSD with ichthyosis (NLSDI) patients, no molecular investigation was performed to evaluate whether this truncated protein is expressed in patients’ cells, whether it is still able to localize to LDs, or whether it maintains residual protein activity
We focus on the adipose triglyceride lipase (ATGL) and ABHD5 proteins and their interaction with other LD proteins involved in lipolysis, a highly regulated process causing the release of fatty acids (FAs) from TAGs
Summary
The human body stores excess amounts of biochemical energy in the form of triacylglycerols (TAGs). Growing evidence indicates that LDs play key roles in the cellular handling of other lipids and hydrophobic molecules, such as the storage of hydrophobic vitamins and signaling precursors that are not related to energy homeostasis [12,13]. The accumulation of LDs is associated with oxidative stress in cancer and non-alcoholic fatty liver disease [23,24] Despite questions about this role, LD biogenesis can lower reactive oxygen species (ROS) levels in human cancer. Other biological functions were recently linked to LDs, including protein maturation, storage, and degradation. In mammals (mice), recent studies showed that perilipin 5 (PLIN5) can be temporarily stored in LDs and translocated to the nucleus in order to induce gene expression [28]. We focus the attention on NLSD cells as an excellent model for the study of further LD functions that are gradually emerging beyond energy homeostasis
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