Prostaglandin E receptor subtype 4 : a metabolic player in white adipose tissue remodeling and cholesterol homeostasis

Abstract

Prostaglandin E receptor subtype 4 (EP4) is one of the four identified receptors for prostaglandin E2 (PGE2). It is abundantly expressed in adipose tissue, suggesting an obligatory role of the receptor in adipocyte biology and energy metabolism. Preliminary studies indicated that upon β3-adrenergic stimulation, mice deficient in EP4 have elevated white adipose tissue (WAT)remodeling as defined by prominent presence of multilocular adipocytes and dramatic increase in mitochondrial biogenesis. Mice deficient in EP4 developed spontaneous hypertriglyceridemia and hypercholesterolemia, providing first evidence that EP4 is a key regulator of lipid homeostasis. Hypertriglyceridemia in EP4 deficient mice is attributed to the decreased activation of lipoprotein lipase, a key enzyme responsible for trafficking plasma triglycerides into peripheral tissues resulting in decreased triglyceride clearance. However, the cause of hypercholesterolemia is yet to be determined. The implicit goal of this thesis is to shed light on the role of EP4in adipocyte biology and lipid homeostasis. Specifically, whether or not genetic deletion of EP4 in mice affects β3-adrenergic activated WAT remodeling will be examined–with focus on the role of EP4 in regulating the function and growth of mitochondria and lipid droplets in adipose tissue. Secondly, the cause of hypercholesterolemia in EP4 knockout mice will be determined–with focus on the role EP4 in regulating cholesterol synthesis and elimination. In study I, deficiency of EP4 amplified β3-adrenergic-mediated WAT remodeling. There was exaggerated decrease in lipid droplet size and induction of mitochondrial biogenesis and its activity. This consequently elevated adipose tissue and whole-body metabolic rate and ensued fat mass loss in mice. Such intensified remodeling did not require upregulation of uncoupling protein 1 (UCP1) expression and it only happened in subcutaneous WAT, but not in other fat depots. The exaggerated WAT remodeling by EP4 deficiency was attributable to increased phosphorylation of AMP-activated protein kinase (AMPK)-mediated fat specific protein 27 (FSP27) signaling axis. These findings revealed that EP4 is a novel negative regulator of WAT remodeling and is a powerful mediator that tightly coordinates rates of triglyceride storage and mitochondrial respiratory function in adipose tissue. In study II, mice lacking EP4 developed spontaneous hypercholesterolemia. EP4 deficiency suppressed cholesterol 7α-hydroxylase (CYP7A1) expression via extracellular signal-regulated kinase1/2 (ERK1/2) signaling and caused hypercholesterolemia by limiting hepatic bile acid synthesis. EP4 deficiency also increased de novo cholesterol biosynthesis and altered cholesterol fluxes in and out of the liver. Treatment with the EP4 agonist, CAY10580 (200 μg/kg body weight/day) for three weeks markedly alleviated hypercholesterolemia in mice caused by high fat diet (HFD) by promoting hepatic bile acid synthesis via ERK1/2-CYP7A1 cascade. These findings demonstrated that activation of EP4 is an effective novel strategy to promote cholesterol disposal in the forms of bile acids in order to lower plasma cholesterol levels. Overall, the studies in this thesis revealed the importance of EP4 in adipocyte biology and lipid homeostasis. Greater understanding of EP4 signaling in adipose physiology and lipid metabolism may generate novel targets for treating obesity and its associated metabolic disorders.