PDIp is a major intracellular oestrogen-storage protein that modulates tissue levels of oestrogen in the pancreas

Abstract

E(2) (17β-oestradiol), a female sex hormone, has important biological functions in a woman's body. The pancreas, often considered a non-classical E(2)-targeting organ, is known to be functionally regulated by E(2), but little is known about how oestrogen actions are regulated in this organ. In the present study we report that PDIp (pancreas-specific protein disulfide isomerase), a protein-folding catalyst, can act as a major intracellular E(2) storage protein in a rat model to modulate the pancreatic tissue level, metabolism and action of E(2). The purified endogenous PDIp from both rat and human pancreatic tissues can bind E(2) with a K(d) value of approximately 150 nM. The endogenous PDIp-bound E(2) accounts for over 80% of the total protein-bound E(2) present in rat and human pancreatic tissues, and this binding protects E(2) from metabolic disposition and prolongs its duration of action. Importantly, we showed in ovariectomized female rats that the E(2) level in the pancreas reaches its highest level (9-fold increase over its basal level) at 24-48 h after a single injection of E(2), and even at 96 h its level is still approximately 5-fold higher. In contrast, the E(2) level in the uterus quickly returns to its basal level at 48 h after reaching its maximal level (approximately 2-fold increase) at 24 h. Taken together, these results show for the first time that PDIp is a predominant intracellular oestrogen storage protein in the pancreas, which offers novel mechanistic insights into the accumulation and action of oestrogen inside pancreatic cells.

Identification of the physiological substrates of PDIp, a pancreas-specific protein-disulfide isomerase family member

“…PDIp is a poorly characterized PDI family member highly expressed in the pancreas. It has been shown that this protein can bind and store estrogen (21). However, it remained unclear whether this protein has physiological functions other than binding estrogen.…”

“…In vitro, PDIp exhibits both thiol-disulfide exchange activity (17) and chaperone activity (19,20). Moreover, PDIp can bind estrogen both in vitro and in vivo, suggesting that one of the functions of PDIp is to bind and store estrogen (21). However, our knowledge about physiological functions of PDIp is very limited.…”