Differential regulation of Peroxisome Proliferator Activating Receptors (PPARs) via host and microbial derived processes Restricted; Files & ToC

Druzak, Samuel (Fall 2022)

Permanent URL: https://etd.library.emory.edu/concern/etds/1v53jz26c?locale=en


Nuclear receptors (NRs) are a highly conserved group of ligand regulated transcription factors. In

humans there are 48 members with each member playing unique complementary roles that allow

for generation and maintenance of multicellular life. The peroxisome proliferator-activated

(PPARs) subfamily of NRs regulate metabolism, inflammation, and proliferation, making them

attractive targets to modulate metabolic syndrome, inflammatory disease, and cancer. Many drugs

have been successfully developed to target these receptors specifically to treat metabolic disease

(i.e. fibrates and glitazones). While much of the therapeutic potential of PPARs has been realized,

undesired tissue specific effects as well as an inability to treat the underlying cause of metabolic

disease limit the utility of these treatments and have stifled development of new PPAR modulators.

To address these problems, this present work seeks to elucidate novel mechanisms by which host

proteins and microbes regulate PPARs. We began our characterization by investigating the

mechanism by which PPARs acquire ligand. Previously, our lab has demonstrated that FABP5

enhances PPARδ transactivation in a polyunsaturated fatty acid dependent manner. Here we have

uncovered a member of the STARD family capable of regulating PPAR activity. Our

characterization of the STARD2-PPARδ interaction uncovered a previously unknown role of lipid

transport proteins in directly engaging with and repressing PPARδ activity in a ligand dependent

manner. In parallel, we have also characterized the role that gut flora play in regulating PPAR

activity. We identified a gut derived obesogen delta-valerobetaine (VB). Treatment of mice with

VB results in diet induced weight gain and hepatic steatosis. This phenotype was posited to occur

by inhibiting lipid metabolism and influencing the activity of hepatic PPARs. Here we describe

the molecular mechanism the underpins the observed phenotype and show that VB is capable of

altering carnitine biosynthesis and carnitine shuttling, effectively decreasing lipid metabolism.

Taken together we have identified two novel mechanisms by which host and microbial processes

are able to affect PPAR activity and have uncovered several new targets capable of tuning PPAR

transactivation upstream of directly modulating these receptors.

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