Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

Abstract

It has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. We hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to cholesterol gallstone formation. In the present study, we investigated whether lack of expression of intestinal Apob48 or Apob100 reduces susceptibility to cholesterol gallstones by decreasing intestinal absorption and biliary secretion of cholesterol in male mice homozygous for an "APO-B48 only" allele (Apob 48/48 ), an "APO-B100 only" allele (Apob 100/100 ), or a wild-type APO-B allele (Apob ؉/؉ ) before and during an 8-week lithogenic diet. We found that cholesterol absorption was significantly decreased as a result of the APO-B48 deficiency in Apob 100/100 mice compared with wild-type and Apob 48/48 mice, regardless of whether chow or the lithogenic diet was administered. Consequently, hepatic cholesterol synthesis was significantly increased in Apob 100/ 100 mice compared with wild-type and Apob 48/48 mice. On chow, the APO-B100 deficiency in S tudies in humans and inbred mice have demonstrated that a complex genetic basis determines the individual and strain predisposition to develop cholesterol gallstones in response to environmental factors. 1 The primary pathophysiological defect involved in cholesterol gallstone formation is increased biliary secretion of cholesterol from the liver, which produces bile supersaturated with cholesterol. 2 Subsequently, biliary cholesterol precipitates as "anhydrous" and monohydrate crystals, which grow and agglomerate toward the formation of macroscopic stones in the gallbladder. Biliary cholesterol is mostly derived from circulating lipoproteins, which originate from the hepatic uptake of plasma high-density lipoprotein (HDL) and chylomicron remnants. [3][4][5][6][7][8] Thus, the potential interrelationship between lipoprotein metabolism-related genes and cholesterol gallstones requires further investigation. In particular, it has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. 9-12 Therefore, we hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to the formation of cholesterol gallstones. APO-B has two different isoforms, APO-B48 and APO-B100, and plays a particularly critical role in the Abbreviations: APO, apolipoprotein; HDL, VLDL, LDL, mRNA, messenger RNA.

Decreased Expression of Cholesterol 7α-Hydroxylase and Altered Bile Acid Metabolism in Apobec-1−/− Mice Lead to Increased Gallstone Susceptibility

“…Our findings demonstrate alterations in bile acid pool size and composition, which, combined with increased biliary cholesterol secretion, increase bile lithogenicity in Apobec-1 Ϫ/Ϫ mice. The current findings, however, are in stark contrast to the phenotype reported in Apob 100/100 mice where these animals were protected against diet-induced gallstones (19). Furthermore, and also somewhat unexpectedly, our findings suggest that Cyp7a1 gene expression is reduced in Apobec-1 Ϫ/Ϫ mice, most likely at a post-transcriptional level.…”

“…Taken together, these findings suggest that the increased susceptibility to gallstone formation noted in Apobec-1 Ϫ/Ϫ mice is unlikely to be attributed to increased cholesterol absorption. Furthermore, our findings fail to confirm the previously documented decrease in cholesterol absorption in both chow and LD-fed Apob 100/100 mice (19).…”

“…In addition, we were intrigued by the findings that mice genetically engineered to express only APOB100 (but which are Apobec-1-sufficient (18)) exhibited protection from cholesterol gallstone formation compared with mice expressing only APOB48, predominantly through decreased intestinal cholesterol absorption (19). However, our findings illustrate a divergence in the phenotype demonstrated in that report (19). We find that Apobec-1…”

“…We also examined the possibility that intestinal absorption of cholesterol might be altered, particularly since studies in Apob 100/100 mice demonstrated a dramatic reduction in cholesterol absorption in LD-fed mice, from ϳ52% in wild type mice to ϳ9% in the Apob 100/100 background (19). Those studies also reported that biliary cholesterol secretion was decreased ϳ2-fold in LD-fed Apob 100/100 mice (19). However, both findings contrast with our results in LD-fed Apobec-1 Ϫ/Ϫ mice.…”

“…In this setting, Apob 100/100 mice were found to be protected against diet-induced gallstones in conjunction with a dramatic reduction in intestinal cholesterol absorption (19). Accordingly, we reasoned that cholesterol absorption might be correspondingly altered in the APOB100-only background associated with Apobec-1 deletion.…”