A Drosophila model of age-dependent ectopic fat accumulation (EFA) has been developed based on the observation that lipid droplet accumulation and relative triglycerides levels change in some tissues in young vs. aged flies. These signs of EFA are observed primarily in the thorax, most noticeably in the jump muscle. In a screen of candidate genes involved in the protein folding-unfolding process or in the unfolding-degradation process, mutations of HDAC6 were identified as specifically modulating age-dependent EFA (phenotypes assessed in young flies vs. old flies).
Dmel\HDAC6, which shares its symbol with the closest ortholog in human, is a cytoplasmic histone deacetylase. HDACs of this type interact with many substrates other than histones, including cytoskeletal proteins and chaperone complex proteins. Dmel\HDAC6 is also closely related to human HDAC10. For Dmel\HDAC6, RNAi-targeting constructs, alleles caused by insertional mutagenesis, and alleles created by targeted recombination, including an amorphic allele, have been generated.
UAS constructs of the human Hsap\HDAC6 gene have been introduced into flies, including wild-type and a modified gene that is catalytically dead, however, they have not been used in the context of this human disease model.
Animals homozygous for an amorphic allele of Dmel\HDAC6 are viable and fertile. They exhibit lipid metabolism phenotypes such as significant age-dependent EFA, lipid composition imbalance, and reduced animal longevity on a high-fat diet. The EFA and longevity phenotypes are ameliorated by a reduction of Dmel\Lsd-2 (see the human disease model report 'obesity, susceptibility to (postulated), PLIN-related' FBhh0000497). It is postulated that transition to EFA depends on regulation of Lsd-2 by HDAC6.
Genetic and physical interactions have been described for Dmel\HDAC6; see the below and in HDAC6 gene report.
[updated Jan. 2018 by FlyBase; FBrf0222196]
The storage of triglyceride droplets in nonadipose tissues is termed ectopic fat storage (Snel et al., 2012; pubmed:22675355).
HDAC6 is a cytoplasmic, class IIb HDAC, known to interact with a number of cytoplasmic proteins, including tubulin and HSP90 (Yao and Yang, 2011; pubmed:21234400).
Many to many: multiple in both species.
High-scoring ortholog of human HDAC6; moderate-scoring ortholog of HDAC10; lower-scoring orthologs in both species. Dmel\HDAC6 shares 33-37% identity and 47-51% similarity with human HDAC6 and HDAC10.
