Current Views on Genetics and Epigenetics of Cholesterol Gallstone Disease

Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.

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The Role of Diet in the Pathogenesis of Cholesterol Gallstones

Current Medicinal Chemistry ◽

10.2174/0929867324666170530080636 ◽

2019 ◽

Vol 26 (19) ◽

pp. 3620-3638 ◽

Cited By ~ 7

Author(s):

Agostino Di Ciaula ◽

Gabriella Garruti ◽

Gema Frühbeck ◽

Maria De Angelis ◽

Ornella de Bari ◽

...

Keyword(s):

Vitamin C ◽

Fast Food ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Gallstone Formation ◽

Protective Role ◽

Cholesterol Homeostasis ◽

Major Health Problem ◽

Cholesterol Gallstones ◽

Beneficial Effects

: Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. : The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.

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Metabolic Syndrome During Menopause

Current Vascular Pharmacology ◽

10.2174/1570161116666180904094149 ◽

2019 ◽

Vol 17 (6) ◽

pp. 595-603 ◽

Cited By ~ 4

Author(s):

Sezcan Mumusoglu ◽

Bulent Okan Yildiz

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Central Obesity ◽

Polycystic Ovary ◽

Ovary Syndrome ◽

Natural Menopause ◽

The Metabolic Syndrome ◽

Increased Risk ◽

Aging Women

The metabolic syndrome (MetS) comprises individual components including central obesity, insulin resistance, dyslipidaemia and hypertension and it is associated with an increased risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The menopause per se increases the incidence of MetS in aging women. The effect(s) of menopause on individual components of MetS include: i) increasing central obesity with changes in the fat tissue distribution, ii) potential increase in insulin resistance, iii) changes in serum lipid concentrations, which seem to be associated with increasing weight rather than menopause itself, and, iv) an association between menopause and hypertension, although available data are inconclusive. With regard to the consequences of MetS during menopause, there is no consistent data supporting a causal relationship between menopause and CVD. However, concomitant MetS during menopause appears to increase the risk of CVD. Furthermore, despite the data supporting the association between early menopause and increased risk of T2DM, the association between natural menopause itself and risk of T2DM is not evident. However, the presence and the severity of MetS appears to be associated with an increased risk of T2DM. Although the mechanism is not clear, surgical menopause is strongly linked with a higher incidence of MetS. Interestingly, women with polycystic ovary syndrome (PCOS) have an increased risk of MetS during their reproductive years; however, with menopausal transition, the risk of MetS becomes similar to that of non-PCOS women.

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Hepatic cholesterol metabolism in cholesterol gallstone disease

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)42070-x ◽

1991 ◽

Vol 32 (3) ◽

pp. 469-475

Author(s):

E Reihnér ◽

B Angelin ◽

I Björkhem ◽

K Einarsson

Keyword(s):

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Hepatic Cholesterol

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Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice

Physiological Genomics ◽

10.1152/physiolgenomics.2000.4.1.59 ◽

2000 ◽

Vol 4 (1) ◽

pp. 59-65 ◽

Cited By ~ 58

Author(s):

BEVERLY PAIGEN ◽

NICHOLAS J. SCHORK ◽

KAREN L. SVENSON ◽

YIN-CHAI CHEAH ◽

JIAN-LONG MU ◽

...

Keyword(s):

Quantitative Trait ◽

Congenic Strain ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Gallstone Formation ◽

Quantitative Trait Loci Mapping ◽

Cholesterol Gallstones ◽

Lithogenic Diet ◽

The Difference ◽

Trait Locus

Quantitative trait locus (QTL) mapping was used to locate genes that determine the difference in cholesterol gallstone disease between the gallstone-susceptible strain C57L/J and the gallstone-resistant strain AKR/J. Gallstone weight was determined in 231 male (AKR × C57L) F1× AKR backcross mice fed a lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butterfat for 8 wk. Mice having no stones and mice having the largest stones were genotyped at ∼20-cM intervals to find the loci determining cholesterol gallstone formation. The major locus, Lith1, mapped near D2Mit56 and was confirmed by constructing a congenic strain, AK.L- Lith1s. Another locus, Lith2, mapped near D19Mit58 and was also confirmed by constructing a congenic strain AK.L- Lith2s. Other suggestive, but not statistically significant, loci mapped to chromosomes 6, 7, 8, 10, and X. The identification of these Lith genes will elucidate the pathophysiology of cholesterol gallstone formation.

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Proinsulin to insulin ratio is associated with incident type 2 diabetes but not with vascular complications in the KORA F4/FF4 study

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001425 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001425

Author(s):

Cornelia Then ◽

Christina Gar ◽

Barbara Thorand ◽

Cornelia Huth ◽

Holger Then ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Metabolic Syndrome ◽

Waist Circumference ◽

Vascular Complications ◽

Model Assessment ◽

Incident Type ◽

The Metabolic Syndrome ◽

Incident Type 2 Diabetes

IntroductionWe investigated the association of the proinsulin to insulin ratio (PIR) with prevalent and incident type 2 diabetes (T2D), components of the metabolic syndrome, and renal and cardiovascular outcomes in the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (2006–2008)/FF4 study (2013–2014).Research design and methodsThe analyses included 1514 participants of the KORA F4 study at baseline and 1132 participants of the KORA FF4 study after a median follow-up time of 6.6 years. All-cause and cardiovascular mortality as well as cardiovascular events were analyzed after a median time of 9.1 and 8.6 years, respectively. The association of PIR with T2D, renal and cardiovascular characteristics and mortality were assessed using logistic regression models. Linear regression analyses were used to assess the association of PIR with components of the metabolic syndrome.ResultsAfter adjustment for sex, age, body mass index (BMI), and physical activity, PIR was associated with prevalent (OR: 2.24; 95% CI 1.81 to 2.77; p<0.001) and incident T2D (OR: 1.66; 95% CI 1.26 to 2.17; p<0.001). PIR was associated with fasting glucose (β per SD: 0.11±0.02; p<0.001) and HbA1c (β: 0.21±0.02; p<0.001). However, PIR was not positively associated with other components of the metabolic syndrome and was even inversely associated with waist circumference (β: −0.22±0.03; p<0.001), BMI (β: −0.11±0.03; p<0.001) and homeostatic model assessment of insulin resistance (β: −0.22±0.02; p<0.001). PIR was not significantly associated with the intima-media thickness (IMT), decline of kidney function, incident albuminuria, myocardial infarction, stroke, cardiovascular or all-cause mortality.ConclusionsIn the KORA F4/FF4 cohort, PIR was positively associated with prevalent and incident T2D, but inversely associated with waist circumference, BMI and insulin resistance, suggesting that PIR might serve as a biomarker for T2D risk independently of the metabolic syndrome, but not for microvascular or macrovascular complications.

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A szexuális funkciózavar és a metabolikus szindróma kapcsolata

Orvosi Hetilap ◽

10.1556/650.2019.31235 ◽

2019 ◽

Vol 160 (3) ◽

pp. 98-103 ◽

Cited By ~ 3

Author(s):

Márta Zsoldos ◽

Attila Pajor ◽

Henriette Pusztafalvi

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Metabolic Syndrome ◽

Sexual Dysfunction ◽

The Metabolic Syndrome ◽

Atherogenic Lipid Profile ◽

Arousal Response ◽

Atherogenic Lipid

Abstract: The prevalence of the metabolic syndrome, type 2 diabetes mellitus, cardiovascular diseases, obesity and depression have increased during the recent years. As the sexual dysfunction is also frequent, we aimed to search for the associations between sexual dysfunction and the metabolic syndrome and its components, respectively, by reviewing the literature. The clinical and biochemical components of the metabolic syndrome included cardiovascular disease, type 2 diabetes mellitus, visceral obesity and depression, furthermore, insulin resistance, atherogenic lipid profile, hypogonadism, chronic systemic inflammation and endothelial dysfunction were all demonstrated to affect adversely the sexual function. The dysfunction of the sexual arousal response shows a strong association in men and a milder one in women with the cardiovascular diseases and depression. Sexual function in diabetes mellitus is mostly impaired by microvascular injury, polyneuropathy and autonomic neuropathy. Erectile dysfunction and disorder of the female sexual arousal response and the orgasm, respectively, are associated with insulin resistance, atherogenic lipid profile and systemic inflammatory condition in overweight or obese patients. Sexual dysfunction particularly in men can be an early sign of the severe complications of metabolic syndrome. The pathogenetic link between the metabolic syndrome and the sexual dysfunction seems to be the insulin resistance. Both metabolic syndrome and sexual dysfunction can be restored by altering the lifestyle. Orv Hetil. 2019; 160(3): 98–103.

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Molecular Mechanisms Underlying the Link between Nuclear Receptor Function and Cholesterol Gallstone Formation

Journal of Lipids ◽

10.1155/2012/547643 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

Mary Carmen Vázquez ◽

Attilio Rigotti ◽

Silvana Zanlungo

Keyword(s):

Nuclear Receptors ◽

Nuclear Receptor ◽

Molecular Mechanisms ◽

Cholesterol Metabolism ◽

Cholesterol Gallstone ◽

Gallstone Disease ◽

Gallstone Formation ◽

Receptor Function ◽

Prevalent Disease ◽

Bile Cholesterol

Cholesterol gallstone disease is highly prevalent in western countries, particularly in women and some specific ethnic groups. The formation of water-insoluble cholesterol crystals is due to a misbalance between the three major lipids present in the bile: cholesterol, bile salts, and phospholipids. Many proteins implicated in biliary lipid secretion in the liver are regulated by several transcription factors, including nuclear receptors LXR and FXR. Human and murine genetic, physiological, pathophysiological, and pharmacological evidence is consistent with the relevance of these nuclear receptors in gallstone formation. In addition, there is emerging data that also suggests a role for estrogen receptor ESR1 in abnormal cholesterol metabolism leading to gallstone disease. A better comprehension of the role of nuclear receptor function in gallstone formation may help to design new and more effective therapeutic strategies for this highly prevalent disease condition.

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The influence of adiponectin and leptin levels on myocardial remodeling in patients with type 2 diabetes mellitus and gout

Clinical Medicine (Russian Journal) ◽

10.18821/0023-2149-2016-94-2-120-127 ◽

2016 ◽

Vol 94 (2) ◽

pp. 120-127

Author(s):

L. A. Sharonova ◽

A. F. Verbovoj ◽

Irina A. Canava ◽

N. I. Verbovaja

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Left Ventricle ◽

Interventricular Septum ◽

Left Ventricular ◽

The Metabolic Syndrome ◽

Number Of Patients

Background. There is a growing number of patients with type 2 diabetes mellitus. As a component of the metabolic syndrome, type 2 diabetes is often associated with hyperuricemia and gout. These diseases worsen prognosis of concomitant cardiovascular disorders. Purpose. To assess the relationship between adiponectin and leptin levels and echocardiographic parameters in patients with type 2 diabetes mellitus, gout, and a combination thereof. Materials and methods. The study involved 30 men aged 41 to 70 years divided into 3 groups. The first group included 10 patients with type 2 diabetes, the second one 10 patients with gout, and the third group consisted of 10 men with a combination of type 2 diabetes and gout. In all patients the levels of glucose, immunoreactive insulin, HOMA-IR, adiponectin, and leptin were measured. All patients underwent echocardiography. Results. The study revealed hyperglycemia in patients with type 2 diabetes and its combination with gout. Patients of all three groups had increased insulin resistance, insulin and leptin levels, deceased concentration of adiponectin. The thickness of interventricular septum in systole and diastole, posterior wall of the left ventricle in diastole, myocarduial mass of the left ventricle, the size of the left atrium and the right ventricle increased in patients of all three groups. Conclusion. The study demonstrated compensatory hyperinsulinemia and insulin resistance, hypoadiponectinemia, hyperleptinemia, left ventricular hypertrophy, diastolic dysfunction, and intact ventricular contractility in patients with type 2 diabetes, gout, and their combination. Hypoadiponectinemia and hyperleptinemia play a role in remodeling of myocardium in these patients.

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