Despite its reputation as an innocent essential mineral, excessive iron intake can be poisonous, and maintaining the proper amount within our cells requires a molecular balancing act among several biochemical pathways. Even at levels that are not overtly toxic, iron overload in humans has been associated with an increased risk of obesity and related conditions, such as type II diabetes and high blood pressure. The reason for the correlation has so far eluded researchers, but research published in the May issue of GENETICS provides insight into iron’s role in fat accumulation.
To find genes involved in animal cells’ response to excessive iron, the study’s authors subjected Caenorhabditis elegans (nematode worms) to high levels of iron while using mutation and RNAi knockdown to test the effects of about 2000 genes. They were searching for genetic variants that affected ftn-1, which encodes a type of ferritin. This protein protects cells against high iron concentrations by binding the mineral, sequestering it away from vulnerable biological molecules. To narrow down this list of ftn-1 modifiers to genes that might shed light on the relationship between iron overload and fat storage, the researchers stained the worms with Nile Red, a dye with an affinity for lipids.
Among the mutant strains with abnormal fat storage, the researchers found that losing function of the gene sgk-1 decreased ftn-1 mRNA levels, while a gain-of-function mutation in the same gene increased the amount of ftn-1 mRNA. This suggests sgk-1 positively regulates ftn-1 expression. When exposed to excessive iron, sgk-1 gain-of-function mutants also had larger lipid droplets and more fat accumulation overall compared to loss-of-function mutants or wild-type, implying that sgk-1 might be a key intermediary in the relationship between iron overload and fat accumulation. This wasn’t a complete surprise: The mammalian orthologs of sgk-1 encode proteins involved in iron homeostasis as well as sugar and lipid metabolism. In humans, a positive correlation has been found between a common sgk-1 variant and obesity, type II diabetes, and hypertension.
Sgk-1 wasn’t the only gene that affected both ftn-1 expression and fat storage. Using the screen data and follow-up experiments, the researchers identified many components of a pathway connecting sgk-1 to iron and lipid uptake. For example, the gene cyp-23A1 seemed to function as a ferritin repressor, likely by decreasing sgk-1 expression. By screening strains with mutations in known lipid transporters, they found that deletion of acs-20, which is an ortholog of a mammalian fatty acid transporter, abolished the fat accumulation associated with excess iron.
This result may explain how iron allows extra fatty acids to enter cells, but one major step was still missing in the new pathway. Once fats get into cells, they need to be ferried to lipid droplets for storage. In search of the missing link, the researchers screened a group of genes homologous to components of mammalian LDL (a.k.a. “bad” cholesterol), called vitellogenins. Deleting one of these genes (vit-2) prevented the lipid droplets from growing after exposure to iron, suggesting that vit-2 was responsible for transporting lipids for storage. And solidifying the notion that vit-2 is part of the new pathway, the researchers found that loss of sgk-1 function nearly abolished vit-2 transcription.
The sgk-1 pathway may be relevant in other organisms, since homologous proteins exist in humans and other animals. And promisingly, sgk1 knockout mice seem physiologically normal; understanding this pathway could provide insight into the relationship between excess iron and lipid storage related problems such as diabetes and heart disease in humans, and—one day—lead to treatments.
Citation:
Wang, H., Jiang, X., Wu, J., Zhang, L., Huang, J., Zhang, Y., Zou, X., Liang, B. (2016). Iron Overload Coordinately Promotes Ferritin Expression and Fat Accumulation in Caenorhabditis elegans.
GENETICS, 203(1), 241-253.
Nicole Haloupek is a freelance science writer and a recent graduate of UC Berkeley's molecular and cell biology PhD program.
View all posts by Nicole Haloupek »Read more in
-
In Memoriam: Ellsworth Herman Grell (1932–2023), a pioneer of Drosophila genome engineering and annotation
Ellsworth (Ed) Grell blessed the Drosophila community through three enduring legacies: as a pioneer of chromosome mechanics, as a primary organizer and synthesizer of genetic knowledge in Drosophila, and as a graceful mentor to those fortunate to have known him personally. Ed grew up in rural Nebraska, completed his undergraduate studies at Iowa State, and…
-
Congratulations to the #Fungal24 Poster Award winners!
We are pleased to announce the recipients of the GSA Poster Awards for posters presented at the 32nd Fungal Genetics Conference! Undergraduate and graduate student members of GSA were eligible for the awards, and a hard-working team of judges made the determinations. Congratulations to all! Felicia Ebot Ojong, The University of Georgia My research is focused…
-
Poster presentation tips for TAGC 2024
You’ve been selected to present a poster at The Allied Genetics Conference 2024 in March—you’ve celebrated, made plans to attend, now what? This is an exciting opportunity to showcase your research and engage with fellow members of the genetics community, so you want to make sure you’re prepared. We wanted to offer you some tips…
-
Maximize your TAGC 2024 experience
A guide to all that National Harbor & DC have to offer Are you joining us for The Allied Genetics Conference 2024 in March? Make the most of your #TAGC24 experience in National Harbor! We know the science will keep you busy, but you deserve to unwind and have some fun, so we’ve curated a…
-
Early Career Leadership Spotlight: Sarah Petrosky
We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates. Sarah PetroskyMultimedia SubcommitteeUniversity of Pittsburgh Research Interest I am interested in understanding adaptation that has been happening recently in populations by dissecting the ways that genes underlying an adaptation…
-
TAGC 2024 Early Career Award Winners
GSA is pleased to announce the winners of the early career awards presented at The Allied Genetics Conference 2024. These awards are specific to particular TAGC communities and recognize early career scientists’ outstanding work on their respective research organisms. The awardees will present their talks in keynote sessions at TAGC 2024. Don’t miss the opportunity…
-
Preeminent geneticists recognized with revamped GSA Awards
In 2022, GSA’s Board of Directors launched an audit to review the five major awards conferred by the Society. Today, we are thrilled to announce the recipients of the reimagined GSA Awards, including the new Genetics Society of America Early Career Medal. The scientists honored this year are recognized by their peers for their outstanding…
-
Fly Board funds outreach programs to spread the word about Drosophila research
In 2020, the Fly Board voted to use part of its reserve fund to support efforts to increase trainee participation as well as equity and diversity in the Drosophila community. An awards committee decides how the money will be spent each year, and from 2020–2022, the committee posted a very broad call for applications from…
-
New members of the GSA Board of Directors: 2024–2026
We are pleased to announce the election of four new leaders to the GSA Board of Directors: 2024 Vice President/2025 President Brenda Andrews Professor, University of Toronto It’s an honor to continue my association with the Society by serving as Vice President of the Board of Directors. I have broad knowledge of the ongoing activities…
-
Parrot plumage study aids breeders and endangered natural populations
Yellow coloration is maladaptive in the wild but prized by breeders. People have long been fascinated with birds, which exhibit one of the widest ranges of coloration among vertebrates. Parrots, in particular, have captivated humans by their ability to mimic human speech and spectacular plumage. Brightly colored feathers are used primarily to attract mates, intimidate…
-
Early Career Leadership Spotlight: Sarah Gilmour
We’re taking time to get to know the members of the GSA’s Early Career Scientist Committees. Join us to learn more about our early career scientist advocates. Sarah GilmourMultimedia SubcommitteeStowers Institute for Medical Research Research Interest Questions of evolution have always fascinated me. I am extremely fortunate to be starting out my research career in a…