Journal News

Identifying a new lipid metabolism gene

Transgelin is an actin-binding protein that promotes motility in cells. What role does it play in lipid metabolism?
Nivedita Uday Hegdekar
April 19, 2022

People with familial hypercholesterolemia, or FH, have very high levels of low-density lipoprotein cholesterol circulating in their blood due to aberrant LDL uptake by cells. With LDL levels elevated for prolonged periods, these patients are at increased risk for atherosclerotic cardiovascular disease.

Transgelin is a protein that in humans is encoded by the TAGLN gene.

“Mutations in several genes have been identified as contributors of FH,” Diego Lucero, a research fellow at the National Institutes of Health, explained. “However, a genetic link is still unidentified in about 20% to 40% of FH patients. This makes diagnosis and drug therapy design more challenging.”

Working in Alan T. Remaley’s lab, which focuses on understanding lipid metabolism and developing therapies to treat cardiovascular diseases, Lucero became interested in identifying other genes that contribute to aberrant LDL metabolism.

Through genomewide CRISPR–Cas9 knockout screening, Lucero used 76,441 sgRNAs to knock out 19,114 genes in Cas9-expressing HepG2 liver cells. sgRNA-transduced cells then were incubated with fluorescently labeled LDL and sorted for LDL uptake through flow cytometry. He collected cells with 5% or lower LDL uptake and deep sequenced them to determine sgRNA representation.

“If a gene influenced LDL uptake, its sgRNAs would feature among the most enriched in the deep sequencing,” Lucero said.

By studying sgRNA enrichment in his cell populations, Lucero identified 15 genes that influenced LDL uptake. He then generated HepG2 cell lines with these 15 candidate genes removed, and he remeasured LDL uptake in these cells.

“As expected, knockout of the LDLR gene showed the most robust reduction (about 80%) in cellular LDL uptake,” said Lucero. “We also observed consistent reductions in LDL uptake in three other novel genes.”

One of the three was transgelin.

Lucero worked with collaborators at the Mayo Clinic to validate the gene hits through the Global Lipids Genetics Consortium and lipid-related phenotypes available in UK Biobank. They found that differences in transgelin expression in human populations were associated strongly with elevated plasma lipids (triglycerides, total cholesterol and LDL cholesterol), making transgelin a target for further investigation. However, transgelin is an actin-binding protein that promotes motility in cells. What role does it play in lipid metabolism?

“In transgelin knockout cells, we found a universal 30% reduction in uptake of LDL, very low-density lipoprotein and transferrin,” Lucero said. “This led us to believe that transgelin affects something common between these cargos.”

When LDL binds to the LDL receptor, the latter is internalized, facilitating transport of LDL into the cell through clathrin-mediated endocytosis. And actin filament reorganization is a necessary step during clathrin-mediated endocytosis.

“Our microscopy experiments showed that transgelin plays a vital role during LDLR internalization, most likely by binding to actin filaments during endocytosis,” Lucero said. “This facilitates LDL uptake and consequently affects cellular cholesterol homeostasis.”

These findings recently were published in the Journal of Lipid Research. Lucero plans to continue this project using mice that are genetically modified to lack transgelin.

“We are also studying other proteins besides transgelin that might be involved in the uptake of LDL,” he said. “While this study focused on genes that reduce LDL uptake, we have also identified those that increase LDL uptake. This is an exciting direction because these might be therapeutic targets that could reduce cholesterol in blood.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition monthly.

Learn more
Nivedita Uday Hegdekar

Nivedita Uday Hegdekar is a recent Ph.D. graduate in biochemistry and molecular biology from the University of Maryland, Baltimore.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Mapping the placenta’s hormone network
Journal News

Mapping the placenta’s hormone network

Oct. 21, 2025

Study uncovers how the placenta actively metabolizes not only glucocorticoids but also novel androgens and progesterones, reshaping our understanding of pregnancy and its complications.

Biochemists and molecular biologists sweep major 2025 honors
News

Biochemists and molecular biologists sweep major 2025 honors

Oct. 20, 2025

Recent Nobel, MacArthur and Kimberly Prize honorees highlight the power of biochemistry and molecular biology to drive discovery, including immune tolerance, vaccine design and metabolic disease, and to advance medicine and improve human health.

Spider-like proteins spin defenses to control immunity
News

Spider-like proteins spin defenses to control immunity

Oct. 17, 2025

Researchers from Utrecht University discovered two distinct binding modes of a spider-shaped immune inhibitor found in serum.

A biological camera: How AI is transforming retinal imaging
Feature

A biological camera: How AI is transforming retinal imaging

Oct. 15, 2025

AI is helping clinicians see a more detailed view into the eye, allowing them to detect diabetic retinopathy earlier and expand access through tele-ophthalmology. These advances could help millions see a clearer future.

AI in the lab: The power of smarter questions
Essay

AI in the lab: The power of smarter questions

Oct. 14, 2025

An assistant professor discusses AI's evolution from a buzzword to a trusted research partner. It helps streamline reviews, troubleshoot code, save time and spark ideas, but its success relies on combining AI with expertise and critical thinking.

Training AI to uncover novel antimicrobials
Feature

Training AI to uncover novel antimicrobials

Oct. 9, 2025

Antibiotic resistance kills millions, but César de la Fuente’s lab is fighting back. By pairing AI with human insight, researchers are uncovering hidden antimicrobial peptides across the tree of life with a 93% success rate against deadly pathogens.