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Keywords:

  • bile;
  • cholesterol;
  • gallstones;
  • lipoprotein;
  • liver

Abstract

  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References

Cholesterol available for bile secretion is controlled by a wide variety of proteins that mediate lipoprotein cholesterol uptake and cholesterol transport and metabolism in the liver. From a disease perspective, abnormalities in the transhepatic traffic of cholesterol from plasma into the bile may influence the risk of cholesterol gallstone formation. This review summarizes some recent progress in understanding the hepatic determinants of biliary cholesterol secretion and its potential pathogenic implications in cholesterol gallstone disease. This information together with new discoveries in this field may lead to improved risk evaluation, novel surrogate markers and earlier diagnosis, better preventive approaches and more effective pharmacological therapies for this prevalent human disease.

The liver plays a critical role in plasma lipoprotein metabolism and is a key organ implicated in body cholesterol removal into the bile. From a disease perspective, alterations in the normal transhepatic traffic of cholesterol from plasma into the biliary system may lead to cholesterol gallstone formation and predispose to dyslipidaemia and atherosclerosis.

The liver acquires cholesterol from endogenous synthesis and plasma lipoproteins and is the most important organ involved in cholesterol disposal (Fig. 1). Cholesterol from plasma lipoproteins is obtained via lipoprotein endocytosis and selective lipoprotein cholesterol uptake mediated by the interaction of apolipoproteins with various liver cell surface molecules, including the low-density lipoprotein (LDL) receptor (LDLR), LDLR-related protein (LRP), hepatic lipase, proteoglycans and scavenger receptor class B type I (SR-BI) (Fig. 1). After uptake, cholesterol can be assembled in liver cell membranes or esterified with fatty acids for intracellular storage in lipid droplets or secretion in very low-density lipoproteins (VLDL). Excess of hepatic cholesterol can be converted into bile acids and secreted both as bile salts and unesterified cholesterol into the bile.

image

Figure 1.  Molecular determinants of transhepatic cholesterol flux. The liver plays a critical role in plasma lipoprotein metabolism and is a key organ implicated in body cholesterol removal into the bile. Multiple cholesterol transport-related gene products, including, among others, apolipoproteins (apoA I–II, apoB, apoE), lipoprotein receptors (LDLR, LRP, SR-BI), intracellular cholesterol binding proteins (NPC1, NPC2, SCP2), enzymes (hepatic lipase, ACAT2, HMGCoAR, MTP) and membrane lipid transporters (ABCA1, ABCG5/ABCG8, NPC1L1) modulate hepatic cholesterol homeostasis. Thus, cholesterol available for bile secretion is controlled by a variety of proteins that mediate lipoprotein cholesterol uptake and cholesterol transport and metabolism in the liver. ABCA1, ATP-binding cassette transporter A1; ABCG5/ABCG8, ATP-binding cassette transporters G5 and G8; ACAT2, acyl-coenzyme A cholesterol acyltransferase type 2; apoA I–II, apolipoproteins A-I and A-II; apoB, apolipoprotein B; apoE, apolipoprotein E; CETP, cholesteryl ester transfer protein; HDL, high-density lipoproteins; HL, hepatic lipase; HMGCoAR, hydroxymethylglutaryl-coenzyme A reductase; HSPG, heparan sulphate proteoglycans; LDLR/LRP, low-density lipoprotein receptor and LDLR-related protein; MTP, microsomal transfer protein; non-HDL, nonhigh-density lipoproteins; NPC1, Niemann-Pick type C-1 protein; NPC1L1; Niemann-Pick C1-like 1 protein; NPC2, Niemann-Pick type C-2 protein; RAP, receptor-associated protein; SCP2, sterol carrier protein 2; SR-BI, scavenger receptor class B, type I; VLDL, very low-density lipoproteins.

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The most important source of biliary cholesterol is preformed plasma lipoprotein cholesterol, with a less significant contribution of cholesterol generated by hepatic new synthesis or hydrolysis of cholesteryl ester stores (reviewed in (1)). Hepatic cholesterol must be transported within the hepatocyte towards the canalicular region before secretion into the bile (2–5). Multiple cholesterol transport-related gene products, including intracellular cholesterol binding proteins as well as canalicular lipid transporters, mediate this trafficking. Thus, cholesterol available for bile secretion is controlled by a variety of proteins that mediate lipoprotein cholesterol uptake and cholesterol transport and metabolism in the liver and whose expression is coordinated by a series of transcriptional factors, including, among others, sterol responsive element binding proteins (SREBPs), liver X receptor (LXR) and farnesoid X receptor (FXR) (6).

Hypersecretion of biliary cholesterol is the primary pathogenic event underlying cholesterol gallstone disease, a highly prevalent condition in western countries (7–9). On the other hand, impaired transhepatic traffic of cholesterol might lead to hypercholesterolaemia and influence atherosclerotic cardiovascular disease. Interestingly, some epidemiological studies have indicated that cholesterol cholelithiasis is associated with subsequent coronary heart disease (10–12), a link that may indicate the presence of shared hepatic lipoprotein metabolism abnormalities that predispose to these common disease conditions.

This review summarizes some recent progress in understanding the hepatic determinants of biliary cholesterol secretion and its potential clinical implications for cholesterol gallstone disease in humans.

Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion

  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References

The hepatic metabolism of diet-derived cholesterol involves the internalization of chylomicron (CM) remnants by interaction between apolipoprotein (apo)E and several redundant and overlapping uptake mechanisms, including the LDLR, LRP, SR-BI, hepatic lipase and proteoglycans (Fig. 1).

In the liver, apoE not only modulates the internalization of lipoprotein remnants but also influences hepatic cholesterol and triglyceride accumulation, hydroxymethylglutaryl-coenzyme A reductase activity and VLDL secretion in chow-fed mice (13, 14). However, cholesterol transport across the liver was not affected in apoE knockout mice (13). In contrast, cholesterol-fed apoE-deficient mice exhibited an impaired response in biliary cholesterol secretion and were protected against diet-induced gallstone formation (15).

Apolipoprotein E gene isoforms are important determinants of interindividual variations in lipid metabolism and plasma lipoprotein levels and they also appear to regulate bile acid synthesis (16–18). In addition, human apoE variants have been associated with dyslipidaemia and other risks for atherosclerosis and gallstone formation. A recent large metaanalysis has confirmed a positive relation between apoE genotypes (from alleles ɛ2 to ɛ4) and plasma LDL cholesterol levels and coronary heart disease risk (19). Furthermore, several studies have addressed the relevance of apoE gene polymorphisms as a risk factor for gallstone formation. Whereas some early studies reported a significant relationship between apoE4 and gallstone disease (20–22), more recent work has not supported this association (23–29), including a large combined genetic linkage study in high-risk populations for this disease as well as subgroups of gallstone-susceptible and -resistant subjects (30). The most likely explanation for these conflicting findings is a sample selection bias in previous studies. Thus, apoE gene polymorphism analysis is not currently recommended for risk evaluation and decision making for prevention or treatment of gallstone disease.

With regard to the hepatic surface molecules involved in the apoE-mediated cholesterol uptake pathway, preliminary studies of our laboratory indicate that the absence of the LDLR associated with attenuated LRP expression significantly impairs diet-derived biliary cholesterol secretion and gallstone formation in mice (unpublished data). Interestingly, a gene polymorphism in the receptor-associated protein (RAP), a chaperone that stabilizes LRP, has been associated with gallstone disease ((31, 32); however, see (33)). The underlying mechanisms for this association may be the important role of RAP in controlling hepatic LRP expression and remnant lipoprotein metabolism with a subsequent effect on cholesterol availability for biliary secretion. More recently, the expression of the LDLR was also found to be critical for the diet-dependent lithogenic effect due to the activation of the nuclear receptor LXR (34), indicating that normal LDLR-mediated hepatic cholesterol uptake plays an important role in this LXR-facilitated and diet-induced model of gallstone formation.

Beside LRP, heparan sulphate proteoglycans (HSPG) also facilitate binding and clearance of both endo- and exogenously derived triglyceride-rich lipoproteins in the liver by cellular mechanisms that can be either dependent or independent of the LDLR protein family (35). Using liver-specific N-deacetylase/N-sulphotransferase-1-deficient mice that exhibit reduced hepatic heparan sulphation and apoE binding, recent work has established that HSPG are indeed involved in the hepatic clearance of remnant lipoproteins and the maintenance of normal plasma lipids levels (36). However, the precise molecular identity of the HSPGs involved in hepatic lipoprotein uptake remains to be defined (37). If HSPGs end up to be relevant for hepatic lipoprotein metabolism in humans, abnormalities in expression and/or activity of these liver cell surface molecules may lead to dyslipidaemia and atherosclerosis as well as influence biliary cholesterol levels and gallstone risk.

Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion

  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References

On the other hand, cholesterol of endogenous origin transported in LDL and high-density lipoproteins (HDL) can be removed by the liver both via LDLR-dependent lipoprotein endocytosis as well as selective cholesterol uptake mediated by SR-BI (Fig. 1).

Although the LDLR appears to be important for diet- and LXR-induced gallstones in mice (34), our unpublished data indicate that the expression of the LDLR per se, without concomitant changes in the functional activity of transcriptional factors, is not essential for biliary cholesterol secretion and gallbladder cholesterol precipitation. Furthermore, heterozygous familial hypercholesterolaemia (38), LDLR gene polymorphisms (28) and changes in hepatic LDLR expression (39) have not been correlated with susceptibility for cholesterol gallstones.

On the other hand, HDL plays a critical role in reverse cholesterol transport by removing this sterol from peripheral tissues and delivering it to the hepatocytes for disposal from the body through biliary secretion. In rodents and humans, both unesterified cholesterol and cholesteryl esters from plasma HDL are key sources of cholesterol for biliary secretion, either as unesterified cholesterol or after transformation into bile acids (reviewed in (40)). An inverse relationship between plasma HDL cholesterol levels and bile cholesterol saturation has been reported in humans (41). More interestingly, plasma HDL concentrations were negatively correlated with the presence of gallstone disease in several epidemiological studies in humans (42, 43) and inbred mouse strains (44). However, the pathophysiological mechanisms underlying this association have not been defined.

Steady-state HDL cholesterol levels per se are not critical determinants of cholesterol levels in bile. Indeed, deficiency of apoA-I or ABCA1, which control HDL production and levels, does not change biliary cholesterol secretion (45–47). The cholesteryl transfer protein (CETP), which transfers cholesterol from HDL to non-HDL lipoproteins for further uptake by the LDL receptor pathway in the liver, is another metabolic factor that affects plasma HDL levels in higher mammals (Fig. 1). The exact significance of this indirect pathway for HDL-mediated reverse cholesterol transport in controlling biliary lipid secretion is unclear. Interestingly, TaqBI CETP gene polymorphism, which correlates with lower plasma HDL cholesterol, has been associated with cholesterol gallstone disease (48, 49). Even though human CETP expression in mice facilitates hepatic HDL cholesteryl ester uptake, it does not alter biliary lipid output or faecal bile acid excretion under basal conditions (50, 51).

At least two additional hepatocellular surface proteins are involved in HDL cholesterol uptake: the HDL remodelling enzyme hepatic lipase and the HDL receptor SR-BI (Fig. 1). In gallstone-susceptible mice, faster secretion of CM remnant cholesterol from plasma into bile was correlated with increased hepatic lipase activity (52). However, the deficiency of hepatic lipase has no major impact on the availability of lipoprotein-derived hepatic cholesterol for biliary secretion and the normal expression of this enzyme is not essential for diet-induced gallstone formation in mice (53). Even though human hepatic lipase gene polymorphisms influence plasma HDL levels (54), none of them have been linked to gallstone disease.

In contrast, hepatic SR-BI expression modulates cholesterol transport from plasma HDL through the liver into the bile (reviewed in (55)) (Fig. 1). Regarding the potential role of SR-BI in diet-induced gallstone formation, recent studies have reported that cholelithiasis was not significantly different between SR-BI-attenuated or SR-BI-deficient mice compared with appropriate control animals when fed with a high fat and cholesterol diet for ≥1 month (56, 57). Under these specific experimental conditions, hepatic SR-BI expression does not seem to be important for controlling biliary secretion of dietary cholesterol. Because of its most significant effect on HDL cholesterol metabolism, SR-BI is most probably involved in gallstone formation associated with increased HDL-mediated reverse cholesterol transport. This latter suggestion is consistent with the upregulation of SR-BI protein expression found in leptin-treated ob/ob mice (58), in which plasma HDL cholesterol lowering was correlated with increased biliary cholesterol secretion and gallstone formation (59).

More interestingly, transcript and protein levels of SR-BI were increased and associated with a higher cholesterol saturation index in the gallbladder bile obtained from Chinese gallstone patients compared with control subjects (39). Although these findings are consistent with the hypothesis that increased levels of biliary cholesterol may originate from plasma HDL cholesterol by enhanced hepatic uptake mediated by SR-BI, genetic and metabolic studies in additional populations are required to further support the pathogenic role of SR-BI in this human disease. If SR-BI turns out to be a metabolic factor that facilitates gallstone formation, pharmacological inhibition of SR-BI may be a new approach to prevent and treat cholelithiasis, even though it may not be feasible because it may lead to an increased atherosclerotic risk due to impaired reverse cholesterol transport.

Intrahepatic cholesterol trafficking

  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References

The detailed cellular and molecular mechanisms by which hepatic cholesterol is transported through the liver and secreted into bile are essentially unknown, but it is conceivable that different pathways and many gene products participate in this highly complex and regulated hepatocellular process.

Overall, intrahepatic cholesterol can be mobilized by membrane transport vesicles or via diffusible carrier proteins. One candidate for a soluble protein-based cholesterol carrier in the liver is the sterol carrier protein-2 (SCP2) (60) (Fig. 1). This protein promotes the exchange of a wide variety of sterols between membranes in vitro and its expression affects sterol trafficking in some tissue culture systems, including hepatoma cells (61). In rodents, SCP2 gene expression manipulation has shown that hepatic SCP2 regulates biliary cholesterol rather than biliary phospholipid and bile salt secretion (62–64). Consistent with these findings, increased hepatic SCP2 expression levels were detected in mice with a genetic predisposition to gallstone disease due to biliary cholesterol hypersecretion (65) and in patients with gallstones (66, 67). However, SCP2 deficiency did not prevent gallstone formation in mice fed with a lithogenic diet (68), suggesting that the role of SCP2 is not critical for gallstone formation.

The Niemann-Pick type C-1 (NPC1) protein is involved in intracellular trafficking of the endocytosed lipoprotein cholesterol by a vesicle-mediated mechanism (69) (Fig. 1). NPC1(−/−) mice fed a high-cholesterol diet failed to upregulate biliary cholesterol secretion (70). Furthermore, hepatic NPC1 overexpression by adenovirus-mediated gene transfer increased biliary cholesterol secretion in both wild-type mice and cholesterol-fed NPC1(−/−) mice (70). Therefore, NPC1 expression seems to be an important factor regulating the availability of cholesterol at the canalicular membrane before biliary cholesterol secretion. If so, this NPC1-mediated cholesterol transport pathway may be critical for gallstone formation.

In addition, NPC2, a cholesterol-binding protein that is key for normal intracellular trafficking of lipoprotein-derived cholesterol (71) (Fig. 1), is also expressed in the liver and can be detected in murine and human bile (72). Intriguingly, NPC2 was exclusively found in the cholesterol pronucleating glycoprotein fraction of human bile and its levels were dramatically increased in the livers of gallstone-susceptible vs gallstone-resistant mice (72). Thus, the actual role of NPC2 in transhepatic cholesterol transport under normal conditions as well as gallstone disease is unknown.

The Star protein family exhibits cholesterol binding activity and includes various members that are expressed in the liver (73–75). For instance, StarD1 facilitates cholesterol movement from intracellular stores to mitochondrial membranes of hepatic cells, stimulating bile acid synthesis (76). Other members of the family, such as StarD3 (also known as MLN64) and StarD5 seem to be more closely related with endoplasmic reticulum stress and cell apoptosis (77, 78). Indeed, no significant changes in plasma and biliary lipid levels, liver lipid content and distribution and sterol metabolism gene expression were found in StarD3-knockout mice (79). The importance of the sterol trafficking capacity of other Star homologues expressed in the liver (74) for the regulation of hepatic cholesterol metabolism and transport has not been addressed.

The oxysterol binding protein (OSBP) family may also be relevant in hepatic cholesterol traffic. OSBP, the first discovered member of this protein family, is a high-affinity cytosolic receptor for oxysterols (80). OSBP protein homologues were subsequently identified in most eukaryotes. OSBP and conserved OSBP-related proteins (ORP) have been shown to mediate nonvesicular sterol trafficking (81, 82). The OSBP family members appear to associate with membranes, possibly through binding to phosphoinositides, and their subcellular localization seems to be controlled by sterol homeostasis (82). This protein family has been implicated in the metabolic regulation of various lipids, including cholesterol and sphingomyelin (83). In fact, overexpression of OSBP (84), ORP2 (85, 86) and ORP4 (87) modulates cholesterol metabolism in cultured cells.

Intrahepatic cholesterol processing pathways

  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References

The availability of hepatic cholesterol for secretion into bile is not only dependent on lipoprotein cholesterol uptake and intracellular cholesterol transport but it is also regulated by its utilization into several metabolically active pathways within the liver. In this regard, gene products involved in cholesterol synthesis and esterification, cholesteryl ester hydrolysis, bile acid biosynthesis and VLDL production and secretion may play an important role in the regulation of cholesterol secretion into the bile in physiological and pathophysiological conditions.

The microsomal triglyceride transfer protein (MTP) is critical for the assembly and secretion of VLDL (Fig. 1). Hepatic MTP inactivation attenuated diet-induced gallstone formation in mice, presumably as a consequence of increased biliary phospholipid secretion that led to the formation of cholesterol-unsaturated gallbladder bile (88). These findings are consistent with the increased activity of hepatic MTP detected in patients with gallstone disease (89). The potential clinical use of pharmacological inhibitors of MTP (90) on human gallstone disease needs further evaluation.

Acyl-CoA:cholesterol acyltransferase (ACAT) is a key enzyme that controls excessive accumulation of intracellular unesterified cholesterol. Two different genes encode ACAT activity, with ACAT2 being most abundantly expressed in the liver and in the intestine (91–93) (Fig. 1). Based on previous nutritional and pharmacological manipulations in animal models (94–97), hepatic ACAT activity was proposed as a major regulator of biliary cholesterol secretion by controlling its availability within the metabolically active cholesterol pool of hepatocytes. Furthermore, ACAT activity in the liver has been inversely correlated with the presence of cholesterol gallstones in humans (98). In addition, complete deficiency of ACAT2 caused resistance to diet-induced gallstone formation in mice (99). However, recent work using specific antisense oligonucleotides to attenuate liver ACAT2 expression did not show significant changes in biliary cholesterol secretion in the rat (100).

Cholesteryl ester hydrolases mediate the hydrolysis of hepatocellular cholesteryl esters, generating unesterified cholesterol that may be used in the liver for further metabolism. Recent work indicates that neutral cholesteryl ester hydrolase regulates bile acid formation and secretion in an SR-BI-dependent manner, rather than the regulating the biliary output of the unesterified cholesterol (101). On the other hand, the role of cholesteryl ester hydrolysis mediated by hepatic hormone-sensitive lipase (102) on biliary cholesterol levels remains to be determined.

Biliary cholesterol secretion

  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References

Specific canalicular membrane transporters participate in biliary cholesterol secretion (103). ABCG5 and ABCG8 transporters represent the canalicular sterol export pumps that function as obligate heterodimers (104), promoting biliary cholesterol secretion and determining cholesterol efflux from hepatocytes into the bile (Fig. 1). Interestingly, hepatic ABCG5 and ABCG8 expression are coordinately regulated with biliary cholesterol secretion and gallstone formation in various experimental models (105–109). Genetic manipulation of ABCG5/ABCG8 expression has definitively established the essential role of these canalicular transporters in biliary cholesterol secretion (110, 111). Remarkably, cholesterol-supersaturated bile was found in ABCG5/ABCG8 transgenic mice even though cholesterol precipitation was not evident (110), indicating that biliary cholesterol hypersecretion alone is not sufficient for inducing gallstone formation in mice.

In addition, a lithogenic ABCG5/ABCG8 allele was associated with cholesterol gallstone formation in gallstone-susceptible inbred mice (112). Moreover, increases in liver ABCG5/ABCG8 expression and biliary cholesterol secretion seem to explain the promotion of cholesterol gallstone formation in a hepatic insulin-resistant mouse model (113). These findings suggest a potential ABCG5/ABCG8-based mechanism for the clinical association between insulin resistance, metabolic syndrome and gallstone disease (114–116). In humans, upregulation of ABCG5/ABCG8 gene expression has been reported in gallstone patients (39). Furthermore, genetic studies, including genome-wide association analysis, have identified the hepatic cholesterol transporter ABCG5/ABCG8 system as a susceptibility factor for human gallstone disease (117–120), suggesting that indeed ABCG5/ABCG8 expression is relevant for cholesterol transport into the bile under normal and pathophysiological conditions. This information may eventually find its way to be used in routine clinical practice.

Recent studies have suggested that the cholesterol transporter NPC1L1, a key determinant of intestinal cholesterol absorption (121), may be directly relevant in the regulation of biliary cholesterol levels in human livers. In humans and other primates, but not in rodents, NPC1L1 is expressed in both the intestine and the liver (121, 122). Interestingly, NPC1L1 localizes in the canalicular membrane of primate hepatocytes and redistributes from an intracellular into an apical compartment after cholesterol depletion, facilitating cholesterol uptake in human hepatoma cells (122) (Fig. 1). More remarkably, hepatic overexpression of NPC1L1 resulted in selective and dramatic reduction in biliary cholesterol secretion, which returned to normal levels after administration of ezetimibe, a pharmacological inhibitor of NPC1L1 (123). These findings suggest that NPC1L1 may transport cholesterol from the canalicular bile back into hepatocytes, counterbalancing the effect of ABCG5 and ABCG8 and protecting against excessive biliary loss of cholesterol from the body (Fig. 1).

Because altered ABCG5/ABCG8 and NPC1L1 expression and/or function in the canalicular domain of liver cells might play a critical role in the pathogenesis of cholesterol gallstones, these transporters represent novel metabolic markers as well as attractive drug targets for prevention and treatment of human cholelithiasis.

Conclusion

  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References

Significant advances have occurred since the time biliary cholesterol secretion was conceived as a relatively simple protein-independent physicochemical process. The current knowledge together with new discoveries in this field will provide new insights for understanding normal biliary cholesterol secretion and its alterations during cholesterol gallstone formation. From a clinical perspective, this information should lead to improved risk evaluation, novel surrogate markers and earlier diagnosis, better preventive approaches and more effective pharmacological therapies for this prevalent human disease.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References

We acknowledge the contribution of many colleagues who have participated in our studies and generated with helpful discussions. Our work is supported by research grants #1070622 (to S. Z.) and #1070634 (to A. R.) from the Fondo Nacional de Desarrollo Científico y Tecnológico (Chile).

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  1. Top of page
  2. Abstract
  3. Remnant lipoprotein cholesterol uptake pathways that influence biliary cholesterol secretion
  4. Low-density lipoprotein and high-density lipoprotein cholesterol uptake and biliary cholesterol secretion
  5. Intrahepatic cholesterol trafficking
  6. Intrahepatic cholesterol processing pathways
  7. Biliary cholesterol secretion
  8. Conclusion
  9. Acknowledgements
  10. References
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