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Ellagic acid (EA) is a polyphenol found in various fruits and plants, such as berries, pomegranates, muscadine grapes, nuts and bark of oak tree. EA has been known to exhibit anti-inflammatory and anti-proliferative effects in various types of cancer. However, little is known about the effects of EA on obesity. Herein, 1) the lipid-lowering role of EA was identified in primary human adipose stem cells (hASCs) and human hepatoma Huh7 cells; 2) the molecular mechanisms by which EA attenuates adipogenesis by epigenetic modification were identified; 3) the effects of EA on high fat and high sucrose-mediated obesity was determined in young C57BL/6J mice; and 4) the potential role of urolithins (Uro), metabolites of EA, in attenuating adipogenesis and lipogenesis of adipocytes were investigated.
In this dissertation research, I firstly identified the novel inhibitory roles of EA on hypertrophic (increase in fat cell size) or hyperplastic (new fat cell formation) adipocyte expansion. 10 mM of EA treatment significantly repressed hypertrophic lipid accumulation by inhibiting de novo lipogenesis of fatty acid in mature adipocytes. The anti-lipogenic effects of EA was also confirmed in Huh7 cells. EA were able to reverse the exogenous fatty acid-induced hepatic triglyceride (TG) accumulation by increasing b-oxidation. These results suggested that EA exerts TG-lowering effects both in adipose tissue and liver. Intriguingly, EA were also able to repress adipogenic conversion of hASCs by blocking early adipogenic markers. Since epigenetic modification has been recently revealed to be a key mechanism regulating adipocyte differentiation, chromatin modifying enzymes were measured. Inhibition of adipogenic conversion of EA was accompanied with augmentation of histone deacetylase (HDAC) 9 and reduction of histone methyltransferase (coactivator associated arginine methyltransferase 1, CARM1) activity. Next, we confirmed lipid-lowering effects of EA in vivo. High fat and high sucrose diet for 12 weeks resulted in a significantly increase in; 1) body weight, 2) plasma cholesterol and TG levels, 3) hepatic endoplasmic reticulum (ER)/oxidative stress, and 4) adipose inflammation, which were normalized by EA-containing raspberry seed flour (RSF) supplementation without altering food intake. Furthermore, systemic levels of glucose and insulin tolerance and hepatic insulin sensitivity were improved by RSF. Finally, to determine whether Uro, gut microbiota-derived metabolites from of EA, displays anti-adipogenic and anti-lipogenic effects of EA in adipocytes, UroA, B, C, D, and iso-UroA were added to differentiating and differentiated hASCs. UroA, C and D are biologically active gut metabolites of EA exerting potent lipid-lowering effects in adipocyte similar to EA. Overall, these data suggest that EA is a potent dietary factor to attenuate obesity and Uro may be novel metabolites manifesting EA’s effects.
Advisor: Soonkyu Chung
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