David Sherman

FSP1-mediated lipid droplet quality control prevents neutral lipid peroxidation and ferroptosis - Nature Cell Biology Lange et al. identify a lipid droplet quality control pathway in which FSP1 safeguards stored neutral lipids from lipid peroxidation, thereby preventing the induction of ferroptosis.

Excited to share our study out in @natcellbio.nature.com! Led by @mikelangelipid.bsky.social, we identify the first #LipidDroplet lipid quality control pathway: LD-localized FSP1 protects stored lipids from oxidative damage and prevents LD-initiated #ferroptosis.
www.nature.com/articles/s41...

We propose a model in which I148M and CGI-58 function at the nexus of two pathways critical for clearing hepatic TG – lipolysis and VLDL secretion – contributing to our understanding of how I148M increases risk for fatty liver disease.
Thank you to the co-authors and my postdoc mentor, Ray Deshaies!

Membrane fluidity is a biophysical property that is important for the biogenesis and secretion of VLDLs, which require substantial membrane deformations and changes along the secretory pathway. As a result of impaired VLDL secretion, TG builds up intracellularly in lipid droplets... Thread 🧵 4/5

ApoB is the main scaffolding protein found in all very low-density lipoprotein (VLDL) particles. We found that, through its sequestration of the lipolytic activator ABHD5/CGI-58, I148M causes a shift in cellular lipid composition that causes reduced membrane fluidity... Thread 🧵 3/5

However, it has proven challenging to elucidate the function of the wild-type protein and what goes awry with I148M to cause hepatic triglyceride (TG) accumulation.
Here, my colleagues and I show that liver cells expressing endogenous I148M have impaired secretion of ApoB...
Thread 🧵 2/5

PNPLA3-I148M is a neomorph that interferes with two primary hepatic triglyceride clearance pathways Sherman et al. show that the common fatty liver disease risk factor PNPLA3-I148M impairs hepatic lipoprotein secretion by altering cellular membrane dynamics. This effect is mediated by a protein that...

I’m happy to share our latest paper on the function of PNPLA3-I148M, the most significant genetic risk factor for fatty liver disease (MASLD).

www.cell.com/cell-reports...

Many groups have tried to determine the function of PNPLA3 and its disease variant (I148M) since 2008...

Thread 🧵 1/5

Really inspiring talk! Thank you.

Looking forward to engaging presentations and discussions at #ASBMB25! I’ll be by poster 270 (Abstract 2651) on Sunday highlighting some of our work on the biological function of the strongest known genetic risk factor for fatty liver disease worldwide, PNPLA3-I148M — stop by if you’re interested

A broad-spectrum lasso peptide antibiotic targeting the bacterial ribosome - Nature A new lasso peptide antibiotic exhibits broad-spectrum activity against Gram-negative and Gram-positive bacteria by interfering with bacterial protein synthesis, is unaffected by common resistanc...

Discovery of a new class of natural antibiotics with a new mode of action to address antimicrobial resistance, a major unmet need
@mcmasteruniversity.bsky.social
@nature.com
www.nature.com/articles/s41...

Opinion | Covid’s Deadliest Effect Took Five Years to Appear (Gift Article) What once belonged to all of us now belongs to corporations.

“Back then, the overwhelming public sentiment was: never again. Today, it seems: never what?”—Siddhartha Mukherjee
Exceptional essay
Gift link

www.nytimes.com/2025/03/10/o...

It's an honor to share this year's Passano Award with Ray Deshaies, Ph.D. for the development of PROTACs, a new therapeutic modality that targets proteins for degradation via co-opting the cellular protein recycling machinery.