Emilio Mottillo
Wayne State University, MI·Biochemistry
Fat cells and liver cells constantly decide whether to store fat or release it for fuel, and getting that balance wrong is central to metabolic disease. When storage goes unchecked in obesity, fat spills into tissues where it does not belong, such as muscle and liver, contributing to diabetes and fatty liver disease.
- Fields
Biochemistry
Physiology
Pharmacology
- Topics
PNPLA3 I148M
lipid droplets
triacylglycerol
- Grants
- 1 known grant, through Jun 2027
What they work on
- Determine the molecular basis for ABHD5, an enzyme co-activator, binding normal PNPLA3 and the disease-linked I148M variant, and map where these complexes sit and how they traffic in fat and liver cells using high-resolution fluorescence and transmission electron microscopy.
- Define the protein composition of the ABHD5/PNPLA3 and ABHD5/PNPLA3 I148M metabolons, the assemblies of metabolic enzymes on lipid droplets, and how it shifts with bound ligands, using unbiased proximity proteomics and targeted immunoprecipitation.
- Test what these complexes do to fat metabolism in adipocytes and hepatocytes by combining gain- and loss-of-function genetic models with natural fatty acid and synthetic ABHD5 ligands, reading out flux with isotope tracers and lipid composition with lipidomics.
- Establish whether the gain-of-function PNPLA3 I148M variant promotes cellular retention of triacylglycerol, the main storage fat, through its interaction with ABHD5, as a mechanism for fatty liver disease progression.
More about the research
This project works out the molecular machinery behind that decision, focusing on a protein pair that sits on the surface of the droplets where cells keep their fat.
Why it matters
Fatty liver disease and type 2 diabetes arise when fat accumulates in the wrong tissues, and the PNPLA3 I148M variant is the single strongest known inherited risk factor for fatty liver disease. Clarifying how ABHD5 controls PNPLA3 and this variant, and showing that the interaction can be tuned by fatty acids and synthetic ligands, could reveal targets for drugs that shift the balance between fat storage and release in liver and fat tissue.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Yong-Xu Wang
University of Massachusetts Chan Medical School, MA·Physiology
Test whether a newly identified adipokine, a hormone released by fat tissue, resolves NASH and associated metabolic problems in two different NASH mouse models.
Ren Zhang
Wayne State University, MI·Biochemistry
Determine whether MNADK, the mitochondrial NAD kinase, preserves liver energy balance and insulin sensitivity and reduces risk of NASH and type 2 diabetes, using genetically engineered mouse models.
Bo Wang
University of Illinois Urbana-Champaign, IL·Physiology
Examine how SEC16B, a scaffold protein on the endoplasmic reticulum, regulates the formation of lipid droplets (fat-storage bodies) in liver cells, using cell-culture and in vivo experiments.
The school
Wayne State University: 21 labs on PI Pages, $292M a year on research, 194 research doctorates a year.
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