Mice lacking lipid droplet-associated hydrolase, a gene linked to human prostate cancer, have normal cholesterol ester metabolism

Abstract

Lipid droplets (LDs) are cellular organelles that are important for energy and lipid metabolism (1, 2). LD accumulation is a hallmark of obesity and is linked to the metabolic syndrome and type II diabetes. LD accumulation is central to atherosclerosis development, in which macrophages in arterial walls accumulate cholesterol esters (CEs) in LDs to become foam cells. Finally, LDs accumulate in many carcinomas (3), and LDs and lipid metabolism are connected to renal clear cell carcinoma and prostate cancer (4-8). Abstract Variations in the gene LDAH (C2ORF43), which encodes lipid droplet-associated hydrolase (LDAH), are among few loci associated with human prostate cancer. Homologs of LDAH have been identified as proteins of lipid droplets (LDs). LDs are cellular organelles that store neutral lipids, such as triacylglycerols and sterol esters, as precursors for membrane components and as reservoirs of metabolic energy. LDAH is reported to hydrolyze cholesterol esters and to be important in macrophage cholesterol ester metabolism. Here, we confirm that LDAH is localized to LDs in several model systems. We generated a murine model in which Ldah is disrupted but found no evidence for a major function of LDAH in cholesterol ester or triacylglycerol metabolism in vivo, nor a role in energy or glucose metabolism. Our data suggest that LDAH is not a major cholesterol ester hydrolase, and an alternative metabolic function may be responsible for its possible effect on development of prostate cancer.-Kory, N., S. Grond, S.

Control of Drosophila Growth and Survival by the Lipid Droplet-Associated Protein CG9186/Sturkopf

“…Goo et al (2014) reported a CE hydrolase activity for the murine CG9186 homolog LDAH, and the characterization of one LDAH knockout mouse revealed a significantly increased body weight in female mutant mice (Currall et al, 2018), which is compatible with its function as a lipase. However, these data conflict with the analysis of a second, inde-pendent LDAH knockout mouse, whose characterization did not reveal a TAG or CE metabolism-associated phenotype (Kory et al, 2017). These data also conflict with our data concerning the knock down of CG9186 transcripts by RNAi (Thiel et al, 2013) and the analysis of the null mutant presented here (Figure 1C), both of which resulted in moderately decreased TAG storage levels in adult flies and no prominent change in the TAG storage levels in whole embryos or larvae ( Figures S1D and S1E).…”

“…For mice, the data concerning the role of LDAH in TAG storage regulation is contradictory. One LDAH knockout mouse study did not show any TAG storage differences or other prominent lipid metabolism-associated phenotypes (Kory et al, 2017). Furthermore, the authors reported negative findings from different targeted lipid modifying enzyme activity assays (Kory et al, 2017).…”

“…One LDAH knockout mouse study did not show any TAG storage differences or other prominent lipid metabolism-associated phenotypes (Kory et al, 2017). Furthermore, the authors reported negative findings from different targeted lipid modifying enzyme activity assays (Kory et al, 2017). A second and independent LDAH knockout mouse study, however, revealed a significant weight gain by the mutant female mice as compared to their wild-type littermates (Currall et al, 2018).…”

“…One study identified for the murine LDAH protein a CE hydrolase activity in macrophages (Goo et al, 2014), which are enriched for CE (Ouimet and Marcel, 2012), as are prostate cancer cells (Yue et al, 2014). However, neither of the aforementioned LDAH knockout studies found a corresponding CE storage phenotype in macrophages or other tissues (Currall et al, 2018;Kory et al, 2017). Given the unclear role of CG9186 and its relatives in TAG and CE metabolism, one could speculate that the proteins are operating outside the canonical lipid metabolism, perhaps affecting protein activity and/or stability, as demonstrated for ATGL (Goo et al, 2017).…”

SOD1 activity thresholds and TOR signalling modulate VAP(P58S) aggregation via ROS-induced proteasomal degradation in a Drosophila model of Amyotrophic Lateral Sclerosis

“…To further bolster our findings, we measured levels of oxidized phospholipids in 248 larval brains (TYURINA et al 2000;KAMAT et al 2015;KORY et al 2017). On feeding C155-249 GAL4/+ larvae with 5 mM paraquat, we enriched and detected 9 oxidized 250 polyunsaturated fatty acids (PUFAs), belonging to phosphatidylserine (PS) and 251 phosphatidylethanolamine (PE) ( Fig.…”