Novel Medical Treatments

The presence of a lithogenic bile is primarily a result of a sustained hypersecretion of biliary cholesterol, which has 2 key components: hepatic and intestinal.31 In principle, drugs influencing hepatic synthesis and/or secretion of cholesterol (ie, statins) and/or intestinal absorption of cholesterol (ie, EZT) are potentially able to influence the formation of cholesterol gallstones and to promote dissolution of gallstones.

Inhibition of Hepatic Cholesterol Synthesis by Statins

Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol biosynthesis. They occupy a portion of the binding site of HMG CoA, blocking access of this substrate to the active site on the enzyme.124 Currently available statins in the United States include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and rosuvastatin. Statins seem also to reduce cholesterol secretion and concentration in bile independently of their ability to block hepatic cholesterol synthesis.125-128 Such combined effects of statins on cholesterol homeostasis in the liver and bile might be able to lower the risk of cholesterol gallstones.129-131 Beneficial effects of statins in preventing gallstone formation have been reported in animal studies.132,133 In humans the effect of statins on gallstone disease has been controversial; reduced gallstone formation, decreased cholesterol concentration in bile, and gallstone dissolution following therapy with statins have been reported by some,134-137 but not all, studies.130,138,139 Another 2 small studies have also been conflicting, with either no association between statin use and the risk of gallstones140 or with an effect of statin on gallstones, although the statistical power was small.141 More recently, 2 studies have reassessed the problem of statin use and risk of gallstone disease, and opened new perspectives. In a cohort of US women self-reporting long-term use statins, the risk of cholecystectomy was found to decrease slightly.142 In a case-control analysis using the United Kingdom-based General Practice Research Database and evaluating incident patients between 1994 and 2004, long -term use of statins (1-1.5 years) was associated with a decreased risk of gallstones followed by cholecystectomy, compared with patients without statin use.143 Whether statin use will be part of the medical therapeutic armamentarium in a subgroup of patients with gallstone disease or to prevent gallstone disease in selected patients at risk needs to be investigated further by appropriate clinical studies.

Inhibition of Intestinal Cholesterol Absorption by EZT

The importance of intestinal factors in the pathogenesis of cholesterol gallstones has recently been investigated by several research groups.1,144 Animal studies have shown that when no dietary cholesterol is available, all biliary cholesterol is mainly derived from hepatic de novo synthesis with a limited contribution (less than 15%) to biliary cholesterol secretion. Rather, the small intestine is the site that solely provides the absorption of dietary cholesterol, as well as reabsorption of biliary cholesterol.144 The importance of intestinal absorption of cholesterol for gallstone pathogenesis is supported by the positive correlation between the efficiency of intestinal cholesterol absorption and the prevalence of cholesterol gallstone formation in several strains of inbred mice.34 The protein NPC1L1 is highly expressed in the small intestine and localized along the brush border of the enterocytes in humans and mice.145,146 There is also a significant amount of NPC1L1 in the human liver but not in the mouse liver.146,147 Cholesterol is the most effective substrate of NPC1L1,148 which governs intestinal absorption of cholesterol146 by recycling between endocytic recycling compartment and plasma membrane (Fig. 3).148 Thus, inhibition of cholesterol absorption in the intestine or hepatic uptake of chylomicron remnants has become an attractive possibility to decrease biliary cholesterol secretion and saturation.100 Similar to humans, the abundance of NPC1L1 in the small intestine far exceeded that in other regions of the gastrointestinal tract, liver, and gallbladder in

Selenoprotein

Fig. 3. Mechanisms for cholesterol uptake mediated by the NPC1L1 according to the model proposed by Ge and colleagues.148 The NPC1L1 protein recycles between the plasma membrane facing the extracellular space and the endocytic recycling compartment. If extracellular cholesterol concentration is high, cholesterol is incorporated into the plasma membrane and is sensed by cell surface-localized NPC1L1. NPC1L1 and cholesterol are then internalized together through clathrin/AP2-mediated endocytosis. The clathrin-coated globular vesicles are transported along microfilaments to the endocytic recycling compartment. The role of myosin in this process is unclear. Large quantities of cholesterol and NPC1L1 are subsequently stored within the endocytic recycling compartment. If the intracellular cholesterol level is low, endocytic recycling compartment-localized NPC1L1 moves back to the plasma membrane along microfilaments, and new cholesterol is absorbed. The key role of the NPC1L1 inhibitor EZT is shown at the center of the cell. EZT prevents NPC1L1 from entering the AP2-mediated clathrin-coated vesicles. At this stage, the endocytosis of NPC1L1 is inhibited and cholesterol absorption is decreased. (Adapted from Portincasa P, Di Ciaula A, Wang HH, et al. Medicinal treatments of cholesterol gallstones: old, current and new perspectives. Curr Med Chem 2009;16(12):1531-42; with permission.)

the Golden Syrian hamster.149 EZT-induced reduction in intestinal cholesterol absorption is coupled with a decrease in the absolute and relative cholesterol levels in bile in hamsters fed a high-cholesterol and high-fat diet. These results are consistent with the recent finding that EZT treatment significantly reduced biliary cholesterol saturation in patients with gallstones.47 EZT belongs to the new class of 2-azetidinones approved as a novel hypocholesterolemic drug150 with a potent inhibitory effect on intestinal cholesterol absorption by specifically suppressing the NPC1L1. EZT might therefore play a primary role in the medical treatment or prevention of cholesterol gallstones, as suggested by studies from the authors' group (Fig. 4). In mice, EZT reduces cholesterol and partly phospholipid but not bile salt content in gallbladder bile; all crystallization pathways and phase boundaries in the bile phase diagram remain similar, with or without EZT.47 If EZT is increased, the relative lipid compositions of pooled gallbladder bile samples are progressively shifted down and to the left of the phase diagram, and

Fig. 4. Pathways underlying absorption of cholesterol from the intestinal lumen and its delivery to the liver. High dietary cholesterol through the chylomicron pathway could provide an important source of excess cholesterol molecules for secretion into bile, thereby inducing cholesterol-supersaturated bile and enhancing cholesterol gallstone formation.31,47 EZT significantly suppresses cholesterol absorption from the small intestine via the NPC1L1 pathway.47 This effect should diminish the cholesterol content of the liver, which in turn decreases bioavailability of cholesterol for biliary secretion. ABCG5/G8, ATP-binding cassette (transporter); ACAT2, acyl-CoA:cholesterol acyltransferase isoform 2; APO-B48, apolipoprotein B48; MTTP, microsomal triglyceride transfer protein. See text for details.

Fig. 4. Pathways underlying absorption of cholesterol from the intestinal lumen and its delivery to the liver. High dietary cholesterol through the chylomicron pathway could provide an important source of excess cholesterol molecules for secretion into bile, thereby inducing cholesterol-supersaturated bile and enhancing cholesterol gallstone formation.31,47 EZT significantly suppresses cholesterol absorption from the small intestine via the NPC1L1 pathway.47 This effect should diminish the cholesterol content of the liver, which in turn decreases bioavailability of cholesterol for biliary secretion. ABCG5/G8, ATP-binding cassette (transporter); ACAT2, acyl-CoA:cholesterol acyltransferase isoform 2; APO-B48, apolipoprotein B48; MTTP, microsomal triglyceride transfer protein. See text for details.

enter the 1-phase (protective) micellar zone (which contains an abundance of unsaturated micelles but never solid cholesterol crystals or liquid crystals). Thus, the micellar cholesterol solubility is increased in gallbladder bile with more cholesterol molecules transferred from the cholesterol monohydrate surface into unsaturated micelles. In this environment, gallstones can dissolve.47,151 EZT also protected gallbladder motility function by desaturating bile.47 The physical-chemical mechanisms underlying the beneficial effects of EZT on supersaturated bile, cholesterol crystals, and cholesterol stones differ from those of hydrophilic bile acids such as UDCA, TUDCA and b-muricholic acid. These hydrophilic bile acids enhance dissolution of cholesterol gallstones by promoting the formation of a vesicle-enriched liquid crystalline mesophase.152 Translational studies have shown that EZT (20 mg/d by mouth for 1 month) significantly reduced cholesterol concentration and cholesterol saturation index and retarded cholesterol crystallization in patients with gallstones.47

Animal and preliminary human studies show that EZT by inhibiting NPC1L1-medi-ated intestinal cholesterol absorption also lowers biliary cholesterol secretion, desa-turates bile, and preserves gallbladder motility function, even under conditions of high dietary cholesterol loads.47,151,153 Whether EZT will become a novel and effective cholelitholytic agent (alone or combined with statins and/or hydrophilic bile acids), is a matter of research in future well-designed, controlled, long-term clinical studies.

Agents Effective on NR

Coherent and coordinate activation of sets of genes involved in multiple cellular activities depends on NR, which are ligand-activated transcription factors.154 Lipid-sensing NR govern lipid homeostasis in the hepatobiliary and gastrointestinal systems. Hepatic and biliary lipid metabolism are involved in lipid secretion by the hepatocytes, and are controlled by the oxysterol receptor LXR (the intracellular sensor of cholesterol155) and the bile acid receptor FXR (the intracellular sensor of bile acids156,157). The subtle cellular mechanisms governing lipid homeostasis imply that cells synthesize oxysterols under conditions of cholesterol overload, and oxysterols in turn bind and activate LXR, which acts to reduce systemic cholesterol burden.156-158 In the enterohepatic system FXR is highly expressed and regulates the expression of genes involved in the maintenance of cholesterol, bile acid, and triglyceride homeostasis.159 Liver FXR might become a pharmacologic target for the treatment of cholestasis and cholelithiasis,160 because this NR upregulates the expression of bile acid transporters in the canalicular membrane and of enzymes responsible for bile acid detoxification. Manipulation of NR in the animal model has disclosed novel potential approaches to the problem of cholesterol gallstone disease. FXR is a promising therapeutic target for treating or preventing cholesterol gallstone disease. FXR-null mice are susceptible to cholesterol gallstone formation; activating FXR with the compound GW4064, a specific synthetic ligand, by contrast, increases biliary bile salt and phospholipid concentrations.161 The effect is tightly dependent on FXR-induced regulation of the energy dependent adenosine triphosphate (ATP)-binding cassette (ABC) transporters ABCB11 (for bile salts) and ABCB4 (for phospholipid)162 and is associated with better solubilization of cholesterol, and prevention of solid platelike crystals and stones. Increased propensity to cholesterol crystallization and stone formation in bile has been described in mice following the activation of hepatic LXR and direct upregulation of the major hepatocyte cholesterol canalicular transporters ABCG5 and ABCG8, which together form a heterodimer.163 Future studies need to test if liver-specific FXR agonists and LXR antagonists might be safe and effective in human gallstone disease, as is the case for dyslipidemia, type II diabetes, and several cancers.

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