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...
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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...

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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

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...

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