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Adaptive response of apolipoprotein A-I and A-IV mRNA in residual ileum after massive small bowel resection in rats.

The response of apolipoproteins, which are synthesized mainly in the small intestine, after small bowel resection has not been documented. In this study, we investigated the effect of small bowel resection on the expression of apolipoprotein mRNA in the residual ileum in rats. Wistar rats underwent either an 85% jejunoileal resection or a sham-operation. Plasma concentrations of total and HDL-cholesterol, apolipoprotein A-I and A-IV were measured on days 0, 3, 6, 9, 12, and 16 (surgery on day 1). The abundances of apolipoprotein mRNA in the residual ileum and liver on day 16 were determined. Plasma levels of total and HDL-cholesterol and apolipoprotein A-I and A-IV in resected rats were significantly lower than in sham-operated rats on days 3 and 6. Resected rats showed a significant increase in ileal apolipoprotein A-I (1.2-fold) and A-IV (3.2-fold) mRNA compared with sham-operated animals. Hepatic apolipoprotein mRNA were the same between two groups. These data suggest that the residual ileum adapts to jejunoileal resection by selective increases in apolipoprotein A-I and A-IV expression at a pretranslational stage. The recoveries of apolipoprotein A-I and A-IV in plasma appear to depend, at least in part, on the increased expression of these apolipoproteins in the residual ileum.

these proteins are key components of the reverse cholesterol transport process .
In rats, apo A-I and A-IV are synthesized mainly in the small intestine and to a lesser extent in the liver (10). The small intestine is capable of adaptive changes in its mucosal structure and function. For example , massive small bowel resection, which results in a severe malabsorptive state known as the short bowel syndrome , i s an established animal model of the intestinal adaptation seen after disease or surgery (11). The short bowel syndrome after massive small bowel resection is characterized by malabsorption, diarrhea and body weight loss as a result of a marked decrease in the intestinal absorptive surface area . In response to small bowel resection, the mucosa in the residual small intestine becomes hyperplastic with tall villi, deep crypts, and enhanced absorption per unit length of intestine (12). These changes result in greater absorptive capacity in the residual small intestine, with diminution of malabsorptive nutritional losses . The mucosal adap tation to small bowel resection is stimulated by several factors including circulating hormones and luminal nutrients (13,14). The phenomena of these adaptive changes have been well documented, and the mechanisms for these responses have been extensively studied. However, little is known about the response of apolipo proteins which are synthesized mainly in the small intestine.
In this study, to obtain further information about the intestinal adaptation to small bowel resection, we have investigated the effect of resection on the steady state levels of apo A-I and A-IV mRNA in the residual intestine and liver , and compared these mRNA levels with plasma levels of apo A-I and A-IV . MATERIALS AND METHODS The study protocol was approved by the Hokkaido University Animal Use Committee, and animals were maintained in accordance with the guidelines for the care and use of laboratory animals of Hokkaido University.

Animals
Analyses of plasma cholesterol. Plasma total cholesterol and HDL cholesterol levels were measured by enzymatic methods using Cholesterol C-Test and HDL -Cholesterol-Test, respectively (Wako Pure Chemical Industries, Osaka, Japan). in Fig. 2. The blots had the expected sizes of approximately 28 and 46 kDa for apo A-I and apo A-IV, respectively. Figure 3A   and E mRNA in the liver were the same between sham-operated and resected rats (data not shown). Figure 5 shows the representative Northern blots of hepatic RNA in sham-operated and resected rats.

DISCUSSION
The data obtained in this study clearly indicate that the ileum adapts to massive small bowel resection by selective increases in apo A-I and A-IV mRNA. Fifteen days after the resection ("day 16"), the apo A-IV mRNA in the residual ileum showed a 3.2-fold increase compared with the control whereas the apo A-I mRNA increased only 1.2-fold. The non-parallel increases in apo A-I and A-IV mRNA suggest that the adaptation of apo A-I and A-IV mRNA to the small bowel resection is gene-specific. After massive small bowel resection, the residual ileum undergoes mucosal hyperplasia with increased cell turnover resulting in villus enlargement (11). If the cause of increases in apo A-I and A-IV mRNA in the residual ileum of resected rats had been an increase in number of finally differenti ated enterocytes which located in villus and expressed these apolipoproteins, the degree of increases in apo A-I and A-IV mRNA would have been the same.
Though the mechanism for the increase in apo A-I and A-IV mRNA in the residual ileum after massive small bowel resection is still unclear, there are two possible explanations. The first is that the apo A-IV mRNA in the residual ileum increases in response to increased absorption of dietary fat by enterocytes. There are a number of reports which suggest that the intestinal expression of apo A-IV is regulated by an event associated with the absorption of dietary fat. Hayashi et al.
(20)reported that apo A-IV and chylomicron output in mesenteric lymph increased dramatically after ingestion of dietary lipid, and that this was associated with increased synthesis and secretion of apo A-IV by the small intestine. Elshourbagy et al. (10) and Apfelbaum et al. (21) also showed that apo A-IV synthesis in the rat small intestine increased in response to dietary triacylglycerol and might be under pretranslational control. Thus, if the enterocytes in the residual ileum adapt to massive small bowel resection by increasing fat absorption, this could elevate the apo A-IV mRNA level in the residual ileum. Gordon et al. (22), however, showed that acute triacylglycerol feeding results in a rapid increase in apo A-IV mRNA in the rat small intestine without a corresponding increase in apo A-I mRNA. We observed that the degree of the increase in apo A-I mRNA was less prominent than in apo A-IV mRNA in the residual ileum. The response of apo A-I mRNA to massive small bowel resection may be not associated with fat absorption. Another possibility is that there may be humoral factors which will regulate the adaptation of apo A-I and A-IV mRNA to massive small bowel resection. Mucosal adaptation to bowel resection is known to be stimulated by circulating hormones. Enteroglu cagon is considered as the enterotrophic humoral factor involved in the intestinal adaptation to bowel resection. A number of reports showed increased plasma levels of enteroglucagon (14, 23, 24) and increased levels of ileal proglucagon mRNA (25, 26) after massive small bowel resection in rats. Peptide YY (PYY) has also been postulated to be a trophic factor involved in intestinal adaptation (27, 28). These hormones are synthesized in the L-cells located in the lower bowel (29, 30). Further studies are necessary to test whether these enterotrophic hormones stimu late apo A-I and A-IV expression during intestinal adaptation.
Plasma levels of apo A-I and A-IV decreased 2 to 5 days after massive small bowel reection, followed by the recovery to the control levels. The increases in apo A-I and A-IV mRNA in the residual ileum on the last day of the experiment suggest that the recoveries of plasma apo A-I and A-IV at least partly depend on the increased expression of these apolipoproteins in the residual ileum. The observation that the degree of plasma apo A-IV decrease was more prominent than that of apo A-I may be because the apo A-IV gene is expressed mainly in the small intestine whereas a considerable amount of apo A-I gene is expressed in the liver in addition to the small intestine. Elshourbagy et al. (10) showed that the apo A-IV and A-I mRNA levels in the liver were 12 and 36%, respectively, of that found in the small intestine, although mRNA for both apolipoproteins were most abundant in the small intestine. for HDL-cholesterol levels in plasma. Actually, Li et al. (31) reported a marked decrease in plasma HDL-cholesterol levels in mice whose apo A-I gene was inactivated by gene targeting.
In conclusion, we propose that the rat ileum adapts to massive small bowel resection by selective increases in apo A-I and A-IV expression at a pretranslational stage. These increases may, at least in part, contribute to the recoveries of plasma apo A-I and A-IV levels.
Our special thanks are due to Dr. Fumihiko Horio for providing the anti-rat apo A-I serum. This work was partly supported by the Nutritional Science Institute, Meiji Milk Products Co., Ltd.