Insulin and cholesterol gallstones: New insights for a complex pathogenic relationship

Authors


  • Potential conflict of interest: Nothing to report.

Biddinger SB, Haas JT, Yu BB, Bezy O, Jing E, Zhang W, Unterman TG, Carey MC, Kahn CR. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med 2008;14:778–782.

Abstract

Available at: http://www.nature.com/nm/journal/v14/n7/abs/nm1785.html

Comments

Cholesterol gallstone disease (CGD) is a high-burden condition worldwide, reaching endemic status among Hispanics and American Indians.1 In addition to sex, age, and family history, several metabolic diseases are associated with a high risk of CGD, including obesity and type 2 diabetes mellitus,1 abnormalities that are considered key constituents of the metabolic syndrome (MS).2 Patients with MS have an increased risk of developing cardiovascular disease as well as CGD.3 Consistent with this common pathogenic background, patients with cardiovascular disease have a higher risk of developing CGD compared with the general population.4 Insulin resistance (IR), characterized by hyperinsulinemia with progressive tendency to hyperglycemia, hypertriglyceridemia, and type 2 diabetes mellitus, is considered the central pathogenic mechanism of the MS.2 Epidemiological studies have indicated that IR predisposes to subsequent CGD,5–7 a link that supports the hypothesis that insulin plays a major role in the regulation of cholesterol metabolism and the enterohepatic circulation of biliary lipids.

The primary pathogenic event of CGD is the secretion by the liver of cholesterol supersaturated bile, which leads to cholesterol precipitation and gallstone formation.8 Stone formation in the gallbladder requires additional factors that favor cholesterol crystal formation and stone growth, because not all individuals with cholesterol supersaturation form gallstones. It is also generally accepted that abnormal regulation of gallbladder function has an important pathogenic role in CGD. The two more common abnormalities of biliary lipid metabolism that induce cholesterol supersaturated bile in CGD are (1) increased biliary cholesterol output and (2) decreased bile acid pool and biliary secretion rate.8 The precise relation between IR and CGD remains undefined. To understand the pathogenic mechanism leading to cholesterol gallstone formation in patients with IR, an important question must be answered: What are the effects of insulin and IR state on cholesterol metabolism, enterohepatic circulation of biliary lipids, and gallbladder function? Experimental data support the concept that insulin plays a major role in the regulation of cholesterol metabolism. For instance, IR decreases intestinal cholesterol absorption and increases cholesterol synthesis9 and very low-density lipopotein (VLDL) production.10 Insulin inhibits the expression of Cyp7a1, the enzyme that controls the rate-liming step of bile acid synthesis,11 and IR causes abnormal motility of the gallbladder, further predisposing through this pathogenic mechanism to cholesterol gallstone formation.12

The current accepted pathogenic relationship between IR, cholesterol supersaturated gallbladder bile and CGD is the increase of body cholesterol synthesis and hypersecretion of biliary cholesterol, as found in obesity.13 Therefore, it is likely that IR could play a major role in determining hypersecretion of biliary cholesterol. However, the detailed molecular mechanisms underlying hypersecretion of cholesterol into bile in IR were unknown until recently. In a series of experiments, Biddinger et al.14 showed in mice with hepatic insulin resistance due to disruption of the insulin receptor (LIRKO) that biliary cholesterol output and saturation are increased, a condition that would favor gallstone formation. When these animals were exposed to a lithogenic diet, all animals developed CGD compared with their controls. These same investigators also demonstrated that mice with hepatic IR evolved with dyslipidemia and atherosclerosis when exposed to an atherogenic diet.15 Unexpectedly, LIRKO mice exhibited an increased gallbladder volume and decreased synthesis of bile acids, suggesting that bile flow and/or gallbladder motility were altered in this experimental model.

An increase in liver ABCG5 and ABCG8 expression is a possible mechanism for the induction of cholesterol gallstone formation in this hepatic insulin-resistant mouse model. ABCG5 and ABCG8 stand for the canalicular sterol export pumps that function as obligate heterodimers promoting biliary cholesterol secretion and determining cholesterol efflux from hepatocytes into the bile.16 Genetic manipulation of ABCG5/ABCG8 expression in mice has definitively established the essential role of these canalicular transporters in biliary cholesterol secretion. As demonstrated by Biddinger et al., the increase in liver ABCG5/ABCG8 expression was a direct effect of insulin resistance, because insulin reduced levels of Abcg5 and Abcg8 messenger RNA at subnanomolar concentrations in a dose-responsive manner in rat hepatoma cells. Interestingly, the short 374 bp intragenic region that separates the human Abcg5 and Abcg8 genes is sufficient to mediate this insulin-dependent response, indicating the existence of an insulin-responsive element within this genomic region. Interestingly, a significant interaction between ABCG5 and ABCG8 and insulin action has also been shown in genetic association studies in which polymorphic variants of these transporters have been linked with insulin sensitivity/resistance in humans.17 Hepatic ABCG5/ABCG8 expression is coordinately regulated with biliary cholesterol secretion and gallstone formation in various experimental models.18 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.18 These previous findings are consistent with the work by Biddinger et al. and suggest that ABCG5/ABCG8 expression is indeed relevant for cholesterol transport into the bile under pathophysiological conditions such as IR and MS.

Biddinger et al. also showed that mice with hepatic IR decreased the synthesis of bile acids14 in spite of increased content of hepatic cholesterol and production of cholesterol-rich VLDL particles.15 Disorders in bile acid metabolism have been associated with CGD in human patients, and reduced bile acid pool and biliary secretion rate are conditions that favor the formation of lithogenic bile and consequently cholesterol gallstones in humans.8 An additional intriguing observation of Biddinger et al.'s study is that gallbladder volume increased three-fold in LIRKO mice. Hyperinsulinemia of LIRKO mice could have increased bile flow and/or inhibited gallbladder motility. In fact, insulin induces bile flow,19 and IR is associated with decreased gallbladder emptying.12 It has been recently well established that fibroblast growth factor-15 (FGF15) acting through specific FGF receptors induces gallbladder relaxation (i.e., filling) and at the same time down-regulates bile acid synthesis in mice.20 Further studies are required to elucidate the underlying molecular mechanism responsible for decreased bile acid synthesis, enhanced gallbladder volume, and regulation of cholesterol metabolism in the liver–gut axis of LIRKO mice.

The work of Biddinger et al. has significantly contributed to the effort to demonstrate a pathogenic link between two complications of MS: CGD and atherosclerosis. This work is also relevant in the understanding of the molecular determinants of normal biliary cholesterol secretion and has opened new leads to disclose its alterations during cholesterol gallstone formation in animal models with IR. The pathogenic mechanisms involved in IR-associated CGD in humans appears more complex compared with diet-induced cholesterol gallstones in LIRKO mice. From a human disease perspective, this study should have major implications in unraveling the pathogenesis of CGD in IR-associated conditions. In addition, this study suggests that treatment of IR and MS should decrease the prevalence of this common human disease.

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