Genetics of gallstone disease

Rebholz, Charlotte; Krawczyk, Marcin; Lammert, Frank

doi:10.1111/eci.12935

Cited by 43 publications

(27 citation statements)

References 41 publications

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“…In bile, cholesterol solubility is maintained by mixed micelles containing bile salts and phospholipids, whose concentrations determine the biliary cholesterol saturation degree [20,21]. Beside cholesterol supersaturation resulting either from increased cholesterol concentration, or a drop in bile acid or phospholipid concentrations, the biliary balance can be destabilized by alterations in hepatic protein expression of e. g. transporters like the bile salt export pump (BSEP) or nucleation factors as well as by pathogens [22].…”

Section: Biliary Composition: a Matter Of Proper Balancementioning

confidence: 99%

“…These results suggest a critical role of TH in modulation of SULT2A1 expression and activity in vivo. [10], [16], [22] [35]…”

Section: Ths Impact Enterohepatic Circulation and Detoxificationmentioning

confidence: 99%

“…In recent years, 32 LITH gene variants at 28 loci including ABCG5/8, SULT2A1, SLC10A2 and CYP7A1 were detected [14,15,22]. In liver and intestine, nuclear receptors (NRs) such as farnesoid X receptor (FXR) and pregnane X receptor (PXR) regulate the expression of LITH genes involved in synthesis and transport of cholesterol, bile salts and phospholipids [66].…”

Section: Ths Impact Nuclear Receptor-mediated Lith Gene Expressionmentioning

confidence: 99%

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Thyroid Dysfunction and Cholesterol Gallstone Disease

Kube

Zwanziger

2019

Exp Clin Endocrinol Diabetes

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Cholesterol gallstone disease (CGD) affects 10–15% of the adult population worldwide and the prevalence increases as a result of longer life expectancy as well as rising obesity in the general population. Beside well established CGD risk factors including environmental and genetic determinants (LITH genes), a correlation between thyroid dysfunction and CGD has been suggested in several human and murine studies. Although the precise underlying mechanisms are poorly understood, thyroid hormones may impact bile flow, bile composition and the maintenance of the enterohepatic circulation. Further there is evidence that thyroid hormones possibly impact LITH genes which are regulated by nuclear receptors (NRs). A better understanding of the CGD pathomechanisms might contribute to personalized prevention and therapy of highly prevalent and economically significant digestive disease. This review presents the current knowledge about the association between CGD and thyroid hormone dysfunction.

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Section: Biliary Composition: a Matter Of Proper Balancementioning

confidence: 99%

“…These results suggest a critical role of TH in modulation of SULT2A1 expression and activity in vivo. [10], [16], [22] [35]…”

Section: Ths Impact Enterohepatic Circulation and Detoxificationmentioning

confidence: 99%

Section: Ths Impact Nuclear Receptor-mediated Lith Gene Expressionmentioning

confidence: 99%

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Thyroid Dysfunction and Cholesterol Gallstone Disease

Kube

Zwanziger

2019

Exp Clin Endocrinol Diabetes

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“…The pathogenesis of cholelithiasis is not fully understood. Mutations in the hepatic and intestinal cholesterol transporter ABCG5/G8 are associated with an increased risk of disease 2 . Based on the main chemical composition, gallstones are divided into pigment and cholesterol gallstones.…”

mentioning

confidence: 99%

The role of chemerin in the pathogenesis of cholelithiasis in children and adolescents

Zdanowicz

Ryzko

Bobrus-Chociej

et al. 2020

J Paediatrics Child Health

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Background and aim Adipokines and hepatokines are proteins secreted by adipose tissue and the liver. To date, the levels of adipokines and hepatokines in cholelithiasis have only been evaluated in studies in adult patients. The purpose of our research was to assess the levels of circulating adipokines: chemerin, vaspin, progranulin, retinol‐binding protein 4 (RBP‐4) and hepatokine: fibroblast growth factor 21 (FGF‐21) and to compare their concentrations in paediatric patients with and without cholelithiasis. Methods The prospective study included 54 children and adolescents diagnosed with gallstones and 26 controls. Fasting serum levels of adipokines and hepatokine were determined by enzyme‐linked immunosorbent assays. Results The serum levels of chemerin, FGF‐21 and RBP‐4 were significantly higher in children and adolescents with gallstones compared to the control group. Elevated levels of triglycerides, RBP‐4, and a homeostatic model for assessing insulin resistance (HOMA‐IR) were observed in overweight or obese patients compared to patients with normal weight and cholelithiasis. Chemerin concentrations were increased in the normal‐weight children and adolescents with cholelithiasis compared to the control group. Children and adolescents with gallstones and abnormal weight had significantly higher levels of chemerin, FGF‐21 and RBP‐4 than healthy controls. Conclusion Elevated serum chemerin levels were significantly higher in non‐obese patients with cholelithiasis than in non‐obese controls, suggesting a potential role of chemerin in the development of cholelithiasis in children and adolescents.

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“…Apart from its huge economic burden imposed on the health care system, cholecystectomy is associated with risk of post-operative mortality (7). Studies are warranted to better understand the mechanism underlying gallstone formation and progression for the development of non-surgical therapies to prevent or ameliorate cholelithiasis (10)(11)(12)(13)(14).…”

mentioning

confidence: 99%

Depletion of hepatic forkhead box O1 does not affect cholelithiasis in male and female mice

Feng

Zhu

Lee

et al. 2020

Journal of Biological Chemistry

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Cholelithiasis is one of the most prevalent gastroenterological diseases and is characterized by the formation of gallstones in the gallbladder. Both clinical and preclinical data indicate that obesity, along with comorbidity insulin resistance, is a predisposing factor for cholelithiasis. Forkhead box O1 (FoxO1) is a key transcription factor that integrates insulin signaling with hepatic metabolism and becomes deregulated in the insulin-resistant liver, contributing to dyslipidemia in obesity. To gain mechanistic insights into how insulin resistance is linked to cholelithiasis, here we determined FoxO1's role in bile acid homeostasis and its contribution to cholelithiasis. We hypothesized that hepatic FoxO1 deregulation links insulin resistance to impaired bile acid metabolism and cholelithiasis. To address this hypothesis, we used the FoxO1LoxP/LoxP-Albumin-Cre system to generate liver-specific FoxO1-knockout mice. FoxO1-knockout mice and age- and sex-matched WT littermates were fed a lithogenic diet, and bile acid metabolism and gallstone formation were assessed in these animals. We showed that FoxO1 affected bile acid homeostasis by regulating hepatic expression of key enzymes in bile acid synthesis and in biliary cholesterol and phospholipid secretion. Furthermore, FoxO1 inhibited hepatic expression of the bile acid receptor farnesoid X receptor and thereby counteracted hepatic farnesoid X receptor signaling. Nonetheless, hepatic FoxO1 depletion neither affected the onset of gallstone disease nor impacted the disease progression, as FoxO1-knockout and control mice of both sexes had similar gallstone weights and incidence rates. These results argue against the notion that FoxO1 is a link between insulin resistance and cholelithiasis.

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Genetics of gallstone disease

Cited by 43 publications

References 41 publications

Thyroid Dysfunction and Cholesterol Gallstone Disease

Thyroid Dysfunction and Cholesterol Gallstone Disease

The role of chemerin in the pathogenesis of cholelithiasis in children and adolescents

Depletion of hepatic forkhead box O1 does not affect cholelithiasis in male and female mice

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