To identify genes that regulate the dynamics of lipid droplet (LD) size, we have used the genetically tractable model organism Caenorhabditis elegans, whose wild-type LD population displays a steady state of size with an upper limit of 3 m in diameter. From a saturated forward genetic screen of 6.7 x 10(5) mutagenized haploid genomes, we isolated 118 mutants with supersized intestinal LDs often reaching 10 m. These mutants define nine novel complementation groups, in addition to four known genes (
maoc-1,
dhs-28,
daf-22 &
prx-10). The nine groups are named drop (lipid droplet abnormal) and categorized into four classes. Class I mutants
drop-5 &
drop-9, similar to
prx-10, are up-regulated in ACS-22-DGAT-2-dependent LD growth, resistant to LD hydrolysis, and defective in peroxisome import. Class II mutants
drop-2,
drop-3,
drop-6 &
drop-7, are up-regulated in LD growth, resistant to LD hydrolysis, but not defective in peroxisome import. Class III mutants
drop-1 &
drop-8 are neither up-regulated in LD growth nor resistant to LD hydrolysis, but seemingly up-regulated in LD fusion. Class IV mutant
drop-4 is cloned as
sams-1 and, different to the other three classes, is ACS-22-independent and hydrolysis-resistant. These four classes of supersized LD mutants should be valuable for mechanistic studies of LD cellular processes including growth, hydrolysis, and fusion.