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.
Highlights
Variations in the gene LDAH (C2ORF43), which encodes lipid droplet-associated hydrolase (LDAH), are among few loci associated with human prostate cancer
LDAH/C2Orf43 orthologs localize to lipid droplets via a hydrophobic domain In Drosophila S2 cells and Saccharomyces cerevisiae, LDAH homologs copurify with LD proteins [43, 44]
We found no evidence for a role of LDAH in whole-body energy metabolism
Summary
Variations in the gene LDAH (C2ORF43), which encodes lipid droplet-associated hydrolase (LDAH), are among few loci associated with human prostate cancer. 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. Linkage of the LDAH locus with prostate cancer suggests that loss of the lipid droplet-associated hydrolase (LDAH) function has a role in prostate tumorigenesis. Goo et al reported that LDAH is a CE hydrolase [17] This finding is intriguing inasmuch as recent studies have linked accumulation of CEs in LDs to prostate and breast cancer aggressiveness [18, 19]. Supporting a function in CE metabolism, two other SNPs in LDAH are associated with changes in LDL cholesterol [20, 21]. LDAH is near APOB on chromosome 2, and these SNPs were originally linked to APOB, a confounding factor because APOB is involved in cholesterol metabolism
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