- Research article
- Open Access
Comparative genomics and functional study of lipid metabolic genes in Caenorhabditis elegans
© Zhang et al.; licensee BioMed Central Ltd. 2013
- Received: 18 January 2013
- Accepted: 6 March 2013
- Published: 12 March 2013
Animal models are indispensable to understand the lipid metabolism and lipid metabolic diseases. Over the last decade, the nematode Caenorhabditis elegans has become a popular animal model for exploring the regulation of lipid metabolism, obesity, and obese-related diseases. However, the genomic and functional conservation of lipid metabolism from C. elegans to humans remains unknown. In the present study, we systematically analyzed genes involved in lipid metabolism in the C. elegans genome using comparative genomics.
We built a database containing 471 lipid genes from the C. elegans genome, and then assigned most of lipid genes into 16 different lipid metabolic pathways that were integrated into a network. Over 70% of C. elegans lipid genes have human orthologs, with 237 of 471 C. elegans lipid genes being conserved in humans, mice, rats, and Drosophila, of which 71 genes are specifically related to human metabolic diseases. Moreover, RNA-mediated interference (RNAi) was used to disrupt the expression of 356 of 471 lipid genes with available RNAi clones. We found that 21 genes strongly affect fat storage, development, reproduction, and other visible phenotypes, 6 of which have not previously been implicated in the regulation of fat metabolism and other phenotypes.
This study provides the first systematic genomic insight into lipid metabolism in C. elegans, supporting the use of C. elegans as an increasingly prominent model in the study of metabolic diseases.
- Caenorhabditis elegans
- Lipid metabolism
- Comparative genomics
- Fat storage
Lipids are hydrophobic molecules with thousands of species including fatty acids and fatty acids derivates, e.g., triglycerides, phospholipids, sphingolipids, sterols, and the like. Generally, lipids function as energy storage, components of biological membrane, and signaling molecules, and likewise play a variety of biological roles in almost all aspects of life: growth, development, reproduction, stresses resistance, aging and longevity, etc. . Accordingly, the homeostasis of lipid metabolism must be tightly regulated. Misregulation of lipid metabolism is often associated with many human diseases, particularly metabolic diseases, such as obesity, type 2 diabetes (T2D), cardiovascular diseases (CVD), and non-alcoholic fatty liver (NAFL) [1, 2], all of which are increasingly prevalent both in both developed and developing countries, such as China .
Previous studies have illustrated that the human systems which control appetite, energy partitioning, and the integration of lipid metabolic processes are highly complex and redundant [4, 5]. Therefore, employing animal models is indispensable in further understanding the lipid metabolism and lipid metabolic diseases. In some situations, lower and less complex organisms are particularly useful in providing simpler and clearer views of the fundamental regulation of lipid metabolism as opposed to higher, more complex organisms. Chiefly due to the advantages of rapid generation time over the last decade, easy genetic manipulation and visualization of lipid droplets at whole animal level has made the tiny nematode, C. elegans an emerging model for exploring the biological functions of lipids and the genetic basis of fat storage regulation. To date, research on this organism has uncovered numerous findings in lipids metabolism and the associated fundamental regulatory mechanisms [6–11], thereby prompting further exploration of its utility as an animal model in these types of studies.
As the first multicellular organism to have its genome completely sequenced  and further deeply analyzed C. elegans possesses for biosynthesis of polyunsaturated fatty acids , mono-methyl branched fatty acids , ceramides , phospholipids [17–21], and also the encoding of many lipid binding proteins and transporters . This organism, however, lacks some key genes involved in the biosynthesis of sterol, forcing the worm to obtain it from its diet [23, 24]. To date, however, how many potential lipid metabolic genes and pathways do exist in the C. elegans genome is not known. Likewise and more importantly for its application as an animal model, the genomic and functional conservation of lipid metabolism from C. elegans to humans is unclear, limiting C. elegans’ utility for in depth exploration of the fundamental mechanisms of lipid metabolism and human metabolic diseases.
In the present study, we analyzed genes involved in lipid metabolism in the C. elegans genome by comparative genomics. We first constructed a database containing 471 lipid metabolic genes from the C. elegans genome, and further assigned most of these into different lipid metabolic pathways. Afterward, we systematically compared these genes in the human, Drosophila, mouse, and rat genomes. Ultimately, we took the advantage of RNA-mediated interference (RNAi) to disrupt the expression of most lipid metabolic genes, allowing us to explore the biological roles these play in C. elegans.
Database construction of C. eleganslipid metabolic genes
The biochemical function of the 471 lipid metabolic genes was further annotated with Ensembl BioMart (http://asia.ensembl.org/biomart/martview/dd89899865f812aff4dcd9ad0dfede49), though the 147 human orthologs and 168 lipid genes from KEGG were already annotated (http://www.genome.jp/kegg/). All 471 genes were also checked again in WormBase (Additional file 1: Table S1). Fuxrthermore, the function annotation obtained from ClueGo  showed that 471 lipid genes in C. elegans were not only involved in distinct lipid metabolic processes, but also play multiple roles in response to oxidative stress, aging and longevity, as well as other biological processes (Additional file 2: Figure S1).
Lipid metabolic gene families in C . elegans
Number in database (all/mapped in pathways)
fatty acid desaturase
lipid binding protein
471 genes potentially involved in 16 lipid metabolic pathways in C. elegans
To gain a clearer picture of lipid metabolic pathways in C. elegans, all 16 pathways were further integrated into a lipid metabolism network (Figure 2). Additionally, 303 lipid genes including 147 human orthologs and 156 genes reported in the literature were assigned into the 16 pathways based on their annotated or reported biological function (Figure 2). However, due to a lack of both clear evidence of the precise biological function and detailed information, some genes could not be assigned into any pathway, even though their paralogs were assigned in the same pathway. Subsequently, we constructed the first lipid metabolism network with 16 pathways containing 471 lipid genes from C. elegans (Figure 2).
Only 35 of the 81 CYPs could be assigned into different lipid metabolic pathways (Figure 2). Based on KEGG annotation, cyp-33E2 may function in fatty acid metabolism, though it was reported to be involved in the biosynthesis of eicosanoides derived from eicosapentaenoic acid (EPA) . Therefore, we reassigned cyp-33E2 into the arachidonic acid metabolism pathway (Figure 2). Despite cyp-35B1 being shown as a target of insulin/IGF-I-like signaling (IIS) , and Cyp-31A2 and Cyp-31A3 being involved in the production of lipids required for eggshell formation , their real catalyzing reactions were unclear enough that they could not be assigned into any lipid metabolic pathway.
Genomic comparison of lipid metabolic genes among humans, mice, rats, Drosophila, and C. elegans
Research on animal models has brought numerous powerful and valuable insights to both basic human biology and disease pathology [34–36]. However, under many circumstances, animal models fall short of our expectations, going so far as to result in contradictory or opposite findings. These discrepancies may be due in part to the changes in the conservation of genetically controlled pathways from human to model animals [36–38]. This reality spurred us to inquire about the conservation of lipid metabolism that exists between C. elegans and humans, as well as mice [39, 40], rats [41, 42], and Drosophila[43–46], all of which are commonly used as models to understand the mechanisms and potential therapies for human metabolic diseases.
Conservation of lipid metabolic genes in 5 model organisms
Organisms (lipid genes)
C. elegans(471) Orthologs
Human (581) Orthologs
C. elegans (471)
Conservation of C. eleganslipid metabolic genes in human disease
In humans, 97 of the 581 lipid genes are overlapped with metabolic disease genes (Figure 3C). Similarly, 94 of the 471 C. elegans lipid genes are orthologs of human metabolic disease genes (Figure 3D). Crucially, all 94 C. elegans lipid genes associated with metabolic diseases are completely overlapped with 97 human metabolic disease genes. In mice, rats, and Drosophila, respectively there are 128, 107, and 97 lipid genes associated with metabolic diseases, with 71 genes conserved across all five species (Additional file 5: Table S3). Moreover, 327 of the 471 lipid metabolism genes in C. elegans are also orthologs of human disease genes (Figure 3E), implying that great number of lipid genes are also involved in other disease processes aside from metabolic syndrome.
Investigated of the biological functions of lipid metabolic genes in C. elegansby RNAi
Among the 471 C. elegans lipid metabolic genes, only a small number have been biochemically and functionally characterized, demonstration that they participate into growth, development, dauer formation, aging and longevity, stress responses, and the like. However, the biological functions of most lipid metabolic genes remain unknown. The current Argilent C. elegans RNAi library covers about 86% of the known and predicted genes, providing a powerful tool to further investigate the biological functions of the lipid genes. We opted to take advantage of RNA-mediated interference (RNAi) to disrupt the expression of each lipid gene and investigate easily visible phenotypes including growth, sterility, and fat storage, indicated by Nile Red staining of fixation .
Phenotypes of lipid metabolic genes inactivated by RNAi
LDs LD size
Growth rate variant, lean, sterile
Egg laying defect, growth rate variant, lethal, slim
Primary bile acid biosynthesis
Growth rate variant, slim, lethal, egg laying defect
Steroid hormone biosynthesis,Linoleic acid metabolism,Biosynthesis of unsaturated fatty acids
Growth rate variant, slim, egg laying defect
Egg laying defect, lethal,pale
Growth rate variant, slim, larvae arrest, lethal
Fatty acid metabolism, Glycerophospholipid metabolism
Egg laying defect, lethal
Arachidonic acid metabolism
Growth rate variant, sterile, pale, slim
Biosynthesis of unsaturated fatty acids
Egg laying defect
Egg laying defect
Reduced brood size, growth rate variant (l3-l4,72 h normal)
Growth rate variant, larval arrest, larval lethal,sterile
Synthesis and degradation of ketone bodies
Egg laying defect
Steroid hormone biosynthesis
Growth rate variant (L3,72 h normal)
Synthesis and degradation of ketone bodies
Larval arrest, lethal
Fatty acid synthesis
Larval arrest, lethal
Fatty acid synthesis
Fatty acid synthesis
Pale, slim, egg laying defect
Understanding the lipid metabolism pathways and the involved genes is critical to further study of the biological functions of lipids and the mechanisms of metabolic diseases. A well-known animal model with a sequenced genome, like C. elegans, can provide a systemic genomic review for the whole lipid metabolism network. Several research groups have bioinformatically or functionally characterized one or several lipid metabolism pathways in C. elegans[14, 16, 22, 26, 68, 74–76]. In our study, we created a database of 471 C. elegans lipid metabolism genes retrieved from the KEGG data, WormBase, and the published literature (Figure 1 and Additional file 1: Table S1). According to their annotation and real biological functions, these 471 genes could be designed into 16 lipid metabolism pathways integrated into a network (Figure 2). To our knowledge, ours is the first study to systematically analyze the lipid genes, metabolism pathways, and their biological functions in the animal model C. elegans.
Remarkably, aside from the 471 C. elegans lipid genes, we additionally found 581, 585, 563, and 428 respective lipid genes in the human, mouse, rat, and Drosophila genomes. Comparison of these genes revealed that 237 lipid genes are conserved in all five species. As such, this work provides useful information regarding lipid metabolism that will aid research utilizing C. elegans and other organisms as animal models. Among the 471 C. elegans lipid genes, 345 (73.25%) have orthologs in humans. Conversely, 380 of the 581 (65.4%) human lipid genes had orthologs in C. elegans. Notably, of 97 human lipid genes related to metabolic diseases, 94 have orthologs in C. elegans and 71 genes are conserved in the human, mouse, rate, C. elegans and Drosophila genomes, suggesting that lipid genes involved into metabolic diseases are highly conserved among model organisms. Altogether, these results indicate that C. elegans and humans share high conservation in terms of lipid genes and their roles in metabolic diseases, suggesting that C. elegans is likely a useful and insightful model for use not only in research on the fundamental biology of lipid metabolism, but also exploring the mechanisms of human metabolic diseases.
The C. elegans RNAi library provides numerous benefits to investigate the role of a specific gene. We thus systematically analyzed the biological functions of lipid genes with available RNAi strains. Among 471 lipid genes, nearly 40% genes were reported to affect phenotypes (http://www.wormbase.org), e.g. fat content, dauer, lifespan, brood size, growth, etc. In this study, we only focused on the clearly observable phenotypes of growth, sterility, and fat storage. However, due to the RNAi variation and gene redundancy of a family (Table 1), RNAi of many of the lipid genes displayed inconsistent, weak phenotypes that we excluded from this report. Consistently, however, inactivation of 21 lipid genes by RNAi remarkably affects worm fat metabolism, development, and other phenotypes. Of these 21 lipid genes, 6 genes T19B10.1 (cyp-29A2), T27F6.6, K12H4.5, F25B4.6 (hmgs-1), F56D1.5 (dhs-5) and D2024.3 (elo-3) have not been reported in literature (Table 3). Remarkbly, 19 out of 21 lipid genes (all except K12H4.5 and dhs-5; Table 3), are fairly conserved in humans and C. elegans. Moreover, C05D11.7, fat-6, dhs-16, fasn-1, pod-2, elo-3, and lpin-1 have relationships with human metabolic diseases.
C. elegans lpin-1 encodes a putative phosphatidic acid phosphatase orthologous to human LPIN1 (OMIM: 605518), LPIN2 (OMIM: 605519), and LPIN3 (OMIM: 605520) (http://www.wormbase.org). In humans and mice, Lpin-1 is associated with metabolic syndrome and type 2 diabetes [77–80] and mutations in human LPIN2 cause Majeed syndrome . C. elegans lpin-1 has been implicated in affecting fat storage and the breakdown and assembly of the nuclear envelope [54, 55]. Consistent with the mammalian Lpin1 mutation, inactivation of C. elegans lpin-1 by RNAi displayed resulted in low fat with small size of lipid droplets, as indicted by Nile Red staining (Figure 4). Human patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with increased liver fat content and liver injury . The C. elegans genome contains at least 5 orthologs of the patatin-like phospholipase (Additional file 1: Table S1). Interestingly, RNAi of C05D11.7, an ortholog of PNPLA3 that was considered to encode adipose triglyceride lipase (ATGL) in C. elegans[51, 52], led to higher fat and larger lipid droplets compared with the control in C. elegans (Figure 4), similar to other reports on humans and rodents [83, 84].
Although mboa-7 affects PUFA incorporation into PI , dhs-16 regulates dafachronic acids metabolism , and sptl-1 is involved in the biosynthesis of ceramide , they have not been previously implicated in fat storage. RNAi inactivation of mboa-7 and dhs-16 displayed increased lipid droplets size (Figure 4), whereas RNAi inactivation of sptl-1decreased lipid droplet size. The fat content of all three genes should likewise be measured by other methods (e.g., thin-layer chromatography and gas chromatography (TLC/GC)) in future studies. acs-1 affects the incorporation of monomethyl branched chain fatty acid (C17iso) into phospholipids  and was reported to increase fat mass . RNAi of acs-1, however, indeed decreased the density and size of lipid droplet (Figure 4). Inactivation of let-767 by RNAi led to slower growth (Figure 5), but once the worms reached the late L4 or early young adult stage, they had increased lipid droplets size (Figure 4). Additionally, RNAi of K12H4.5, kat-1, and F25B4.6 resulted in slower growth (Figure 5), but fat storage looked normal once the worm entered into late L4 or early young adulthood. Several members of cytochrome P450 superfamily were reported to functionally affect lipid metabolism [31, 33, 85, 86]. We only found that RNAi of cyp-29A2 significantly decreased fat storage with small lipid droplets as compared with the control (Figure 4). Consequently, these lipid genes should potentially be considered as a starting point to further investigate their role in the regulation of fat storage.
We created a database of 471 C. elegans lipid metabolism genes that could be designed into 16 lipid metabolism pathways integrated into a network. Additionally, 581, 585, 563, and 428 respective lipid genes in the human, mouse, rat, and Drosophila genomes were also retrieved. Over 70% of C. elegans lipid genes have human orthologs, with 237 of 471 C. elegans lipid genes being conserved in humans, mice, rats, and Drosophila, of which 71 genes are specifically related to human metabolic diseases. Furthermore, RNA-mediated interference (RNAi) of 21 lipid genes affects fat storage, development, and reproduction. This study provides the first genomic view on lipid metabolism in C. elegans, supporting the use of C. elegans as an increasingly prominent model in the study of metabolic diseases.
Retrieval of C. eleganslipid metabolic genes and database construction
Most of lipid metabolism genes used in this study were initially downloaded from the KEGG pathway database (http://www.genome.ad.jp/kegg/pathway.html), which has to date collected 168, 407, 383, 333, and 170 lipid metabolic genes respectively from the C. elegans, human, mouse, rat, and Drosophila genomes. Of the 407 human lipid genes present in the C. elegans genome, 364 were orthologs. Another 156 lipid metabolism genes in C. elegans were manually taken from WormBase (http://www.wormbase.org) and the published literature, mainly retrieved from PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). Any overlapping genes were excluded with Perl program manually and online using the Venny program (http://bioinfogp.cnb.csic.es/tools/venny/ index.html). In total, 471 C. elegans lipid genes were been retrieved. The BioMart Interface (http://asia.ensembl.org/biomart/martview/53ac7015dbd78f9a5c2f0a3479fa4dc4) was applied to standardize all gene IDs.
Identification of lipid metabolic genes in human, mouse, rat, and Drosophila
We used 471 C. elegans lipid metabolic genes to search for orthologs in the human, mouse, rat and Drosophila genomes by Ensembl BioMart and found 370, 389, 375, and 352 orthologs in human, mouse, rat, and Drosophila, respectively (Table 2). The KEGG database has collected 407 human lipid metabolic genes to date; after combining these and 370 human orthologs of C. elegans lipid genes, the overlapped genes were discarded. Within the human genome, 581 lipid genes have been found, and we used these in reversely to search for orthologs in C. elegans, mouse, rat, and Drosophila genomes (419, 539, 517, and 340 genes, respectively (Table 2)). The KEGG database contains 383, 333, and 170 lipid metabolic genes for the mouse, rat, and Drosophila genomes, respectively. After combining both sets of lipid genes and discarding any overlapped gene in each organism. In total, 585, 563, and 428 lipid genes could be identified in mouse, rat, and Drosophila genomes, respectively, with the additional 581 lipid genes within the human genome (Additional file 3: Table S2 and Additional file 4: Figure S2).
Annotation of lipid metabolic genes in C. elegans
The 168 lipid metabolic genes we retrieved from the KEGG database were already annotated. The remaining 303 lipid genes were annotated via Ensembl BioMart (http://asia.ensembl.org/biomart/martview/53ac7015dbd78f9a5c2f0a3479fa4dc4), Swiss-Prot/TrEMBL (http://www.expasy.org), and Gene Ontology (http://www.geneontology.org/). However, since the annotation databases are incomplete, if a gene could not be annotated from a database, they were annotated by hand using previously published papers (primarily retrieved from PubMed) and WormBase (http://www.wormbase.org/). Following annotation, the biological functions of all 471 genes were manually back checked via WormBase.
Retrieval and comparison of disease associated genes in humans, mice, rats, C. elegans, and Drosophila
From the NCBI database (ftp://ftp.ncbi.nih.gov/gene/DATA/), 19994 MIM disease ID genes, phenotypes, and locus were downloaded from NCBI ftp. In total, 15181 genes could be mapped by Ensembl Biomart ID Mapping and were therefore considered human disease genes. All metabolic disease genes were searched from OMIM database (http://www.ncbi.nlm.nih.gov/omim/) using the following keywords: Obesity, Diabetes, Metabolic disease, Sleep apnea, Atherosclerosis, Coronary disease, Hyperlipidemia, and Hypertension. After excluding redundant genes, some further 1264 human metabolic disease genes were identified in our database.
Orthologs information of human gene inferred by Ensembl (release 66) ortholog detection pipeline was obtained from Ensemble’s BioMart interface (http://asia.ensembl.org/biomart/martview/53ac7015dbd78f9a5c2f0a3479fa4dc4). Specifically, we retrieved Ensembl identifiers of orthologs to human genes together with identifiers of their translated protein products. Details of the ortholog detection pipeline are described at http://aug2007.archive.ensembl.org/info/data/compara/homology_method.html. Briefly, gene families were identified from all sequences in the database by WU-Blastp and Smith–Waterman searches, followed by construction of a phylogenetic tree for each gene family to identify orthologous and paralogous relationships between gene pairs.
All orthologs of lipid metabolism genes, human disease genes, and human metabolic genes were then compared by using VENNY, an interactive tool for comparing lists with Venn diagrams (http://bioinfogp.cnb.csic.es/tools/venny/index.html).
Worm strains, growth condition, and RNA interference
Standard protocols were used to maintain the C. elegans N2 strain growing at 20°C with E. coli OP50 for food, unless specifically noted. RNAi was performed by feeding bacterial strains from the Ahringer C. elegans RNAi library, obtained from Gene Services (Source BioScience) [88, 89]. The empty vector L4440 in the Ahringer library E. coli HT115 strain was used as the negative control for RNAi experiments. The current Ahringer C. elegans RNAi library covers about 86% of both known and predicted genes. In our C. elegans lipid metabolism genes database, only 356 genes have available RNAi bacterial strains. Generally, eggs were isolated from gravid adults using hypochlorite treatment and hatched in M9 buffer overnight, and then synchronized L1 worms plated onto NGM plates seeded with E. coli strain HT115 carrying the RNAi clone of a specific lipid gene. Worms were occasionally checked after 48 hr. RNAi of 356 genes was carried out for four biological rounds.
Nile Red staining of fixed nematodes to visualize fat storage
Late L4s or young adult nematodes with one or two eggs within their uterus were washed off growth plates, fixed and then stained with Nile Red as described previously [48, 90]. All images were captured using identical settings and exposure time.
Growth rate and sterility analysis
Growth rate analysis was conducted in line with our previous report . All images were captured using identical settings and exposure times. Worms which clearly laid fewer eggs were recorded as having a “egg laying defect”, and those with no eggs were recorded as “sterile”.
We would like to thank other members of our lab for their comments on this manuscript. This work was supported by Chinese Natural Science Foundation to BL (31171134 and U1202223) and to XJ Zou (31160216), as well as Yunnan Natural Science Foundation to XJ Zou (2011FZ179).
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