Homeostasis of circulating retinol

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Circulating retinol concentrations are homeostati-cally regulated to remain constant, despite great variations in the dietary supply and liver stores of vitamin A. The controlled release of vitamin A from liver stores is necessary to provide tissues with optimal amounts of retinol, without releasing excessive amounts which would lead to toxicity. Although various schemes for the homeostasis of circulating retinol have been proposed, an unequivocal mechanism has not yet been established.

The concentration of retinol bound to plasma RBP is maintained within a normal range of concentrations, referred to as its homeostatic set point, as long as there is some minimal concentration of vitamin A

in the liver and in extrahepatic tissues. Thus rats fed a vitamin A-deficient diet maintained a relatively stable plasma retinol level, which did not drop below 30 |g per 100 mL until liver reserves fell below 10 |g g-1 tissue (Underwood et al., 1979). Control of plasma retinol concentration is mediated by factors that affect the balance between retinol input to plasma and retinol output from plasma. Controlling factors include the enzymes that esterify retinol and hydrolyse retinyl esters in the tissues. The activity of hydrolytic enzymes is enhanced during vitamin A deprivation, releasing holoRBP into the bloodstream. The activity of esterifying enzymes, on the other hand, is enhanced when vitamin A intake is plentiful, allowing surplus vitamin A to be stored. Ultimately, the set point for plasma retinol depends on the rate of release of holoRBP from the liver. Underwood proposed that hepatic secretion of retinol is controlled by a signal generated in proportion to the uptake or utilization of retinol in extrahepatic target tissues.

The plasma retinol homeostatic set point is influenced by several dietary and hormonal factors; these include protein, calorie and zinc nutriture, and fluctuating steroid hormone levels that occur during the oestrous cycle or as a result of stress. It is likely that steroid hormones act by influencing the synthesis of RBP (Borek et al., 1981). Ahluwalia et al. (1980) used hypophysectomized rats to demonstrate that without growth there was no vitamin A utilization. They showed that, in addition to dietary protein, growth hormone was required for mobilization of liver vitamin A stores. The data suggested that growth hormone may play an important role in vitamin A homeostasis by regulating retinol entry at the tissue level.

It is well documented that humans with chronic renal failure have elevated plasma levels of retinol. Gerlach & Zile (1990), using rats with surgically induced acute renal failure, established that the rise in plasma retinol was almost entirely due to an increase in retinol associated with RBP. The source of the elevated plasma holoRBP was shown to be an increased hepatic release of the complex and not peripheral uptake (Gerlach & Zile, 1991a). These findings suggest that the kidney has a physiological role in regulating the homeostatic set point for circulating retinol concentrations, possibly by modulating the release of holoRBP from the liver.

Gerlach & Zile (1991b) postulated the following regulatory mechanisms. (1) The intact kidney provides a specific regulatory substance (negative feedback signal) which prevents the release of hepatic holoRBP. In the absence of kidney function the decreased signal will allow the release of holoRBP. (2) A regulatory substance originating in the peripheral tissues (positive feedback signal) is normally removed by the kidney and therefore hepatic holoRBP will not be released. In renal failure the substance will accumulate and elicit the release of holoRBP.

Gerlach & Zile (1991b) investigated the possibility that retinoic acid might be a negative feedback signal released by the kidney or a positive feedback signal from peripheral tissues. The negative feedback hypothesis was tested by administering an exogenous supply of near physiological amounts of retinoic acid to rats with renal failure to compensate for the absence of retinoic acid in circulation owing to lack of kidney function. If this hypothesis was valid, adding retinoic acid to the circulation would restore the negative feedback and plasma retinol levels would be lowered to the normal levels of intact animals. However, the administration of retinoic acid did not alter the elevated plasma retinol levels that occurred in renal failure. The positive feedback hypothesis was tested by increasing the serum levels of retinoic acid at concentrations approximating the upper physiological limit. If this hypothesis was valid, rats with renal failure would respond with a substantial increase in serum retinol concentrations, whereas animals with renal failure that were not treated with retinoic acid would respond in a less pronounced manner. It was found that administration of retinoic acid had no significant effect on the existing serum retinol concentration and it was therefore concluded that retinoic acid does not serve as a negative or positive feedback signal for the release of hepatic retinol.

Another possibility considered by Gerlach & Zile (1991b) was that a positive peripheral feedback signal molecule other than retinoic acid regulates the release of hepatic retinol into circulation. This hypothesis was tested by greatly increasing the serum retinoic acid concentration so that it would be expected to provide peripheral tissues with a sustained high concentration of retinoic acid. Under these conditions, retinoic acid can partially substitute for retinol requirement in peripheral tissues, i.e. exert a sparing effect on retinol utilization. Consequently, peripheral target tissues would have a reduced requirement for retinol and the signal for hepatic retinol release would be decreased. In rats with renal failure a higher amount of this positive feedback signal would remain in circulation compared to the amounts in rats with intact kidneys because the signal is not removed by the kidney. Therefore, if this hypothesis is valid, under conditions of retinoic acid sparing effect on retinol utilization, intact rats as well as rats with renal failure should have lower serum retinol concentrations than their respective controls not given retinoic acid. This depression (sparing effect) should be significantly smaller in rats with renal failure compared with that obtained in intact rats. These effects were indeed observed with decreases in serum retinol concentration of 29% and 19% relative to controls in rats with intact kidney function and with renal failure, respectively. The data supported the hypothesis that a positive peripheral feedback signal other than retinoic acid regulates the release of hepatic retinol.

Gerlach & Zile (1991b) postulated that the positive feedback signal molecule from the periphery is apoRBP, which returns to circulation after reti-nol-RBP-transthyretin is delivered to target tissues and would be a sensitive indicator of the physiological needs of retinol by tissues. The lack of removal of apoRBP by the kidney in renal failure would cause it to accumulate in the circulation, triggering an enhanced release of hepatic retinol. The hypothesis was tested by adding apoRBP to the circulation of rats with renal failure. An observed increase in plasma retinol concentration above that already caused by renal failure was evidence that apoRBP is a positive physiological feedback signal from the periphery for the regulation of release of hepatic retinol into circulation.

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