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Saponins as modulators of nuclear receptors.
Zhang, T, Zhong, S, Li, T, Zhang, J
Critical reviews in food science and nutrition. 2020;(1):94-107
Abstract
As plant-derived natural products, saponins have been widely applied for the dietary modification of metabolic syndrome. However, the underlying mechanisms of their preventive and therapeutic effects are still largely unclear. Nuclear receptors have been identified as potential pharmaceutical targets for treating various types of metabolic disorders. With similar structure to endogenous hormones, several saponins may serve as selective ligands for nuclear receptors. Recently, a series of saponins are proved to exert their physiological activities through binding to nuclear receptors. This review summarizes the biological and pharmacological activities of typical saponins mediated by some of the most well described nuclear receptors, including the classical steroid hormone receptors (ER, GR, MR, and AR) and the adopted orphan receptors (PPAR, LXR, FXR, and PXR).
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2.
Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators.
Fiorucci, S, Zampella, A, Cirino, G, Bucci, M, Distrutti, E
American journal of physiology. Heart and circulatory physiology. 2017;(1):H21-H32
Abstract
Bile acids are end products of cholesterol metabolism generated in the liver and released in the intestine. Primary and secondary bile acids are the result of the symbiotic relation between the host and intestinal microbiota. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals that exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid-activated receptors, GPBAR1 (also known as TGR5) and the farnesosid-X-receptor (FXR), have also been detected in the vascular system and their activation mediates the vasodilatory effects of bile acids in the systemic and splanchnic circulation. GPBAR1, is a G protein-coupled receptor, that is preferentially activated by lithocholic acid (LCA) a secondary bile acid. GPBAR1 is expressed in endothelial cells and liver sinusoidal cells (LSECs) and responds to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-γ-lyase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSECs is due to genomic and nongenomic effects, involves protein phosphorylation, and leads to release of H2S. Despite that species-specific effects have been described, vasodilation caused by GPBAR1 ligands in the liver microcirculation and aortic rings is abrogated by inhibition of CSE but not by eNOS inhibitor. Vasodilation caused by GPBAR1 (and FXR) ligands also involves large conductance calcium-activated potassium channels likely acting downstream to H2S. The identification of GPBAR1 as a vasodilatory receptor is of relevance in the treatment of complex disorders including metabolic syndrome-associated diseases, liver steatohepatitis, and portal hypertension.
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3.
Nuclear receptor variants in liver disease.
Zimmer, V, Liebe, R, Lammert, F
Digestive diseases (Basel, Switzerland). 2015;(3):415-9
Abstract
This snapshot reviews the current state of knowledge on genetic variants of nuclear receptors (NRs) involved in regulating various aspects of liver metabolism. Interindividual differences in responses to diet and other 'in-' and environmental stressors can be caused by variants in components of the NR regulatory gene network. We recapitulate recent evidence for the application of NRs in genetic diagnosis of monogenic liver disease. Genetic analysis of multifactorial liver diseases, such as nonalcoholic fatty liver disease and diabetes mellitus, pinpoints key players in disease predisposition and progression. In particular, NR1H4 variants have been associated with intrahepatic cholestasis of pregnancy and gallstone disease. Other examples include studies of NR1I2 and NR1I3 polymorphisms in patients with drug-induced liver injury and NR5A2 variation in cholangiocarcinoma. Associations of NR gene variants have been identified in patients with dyslipidemia and other metabolic syndrome-associated traits by genome-wide studies. Evidence from these analyses confirms a role for NR variation in common diseases, linking regulatory networks to complex and variable phenotypes. These new insights into the impact of NR variants offer perspectives for their future use in diagnosis and treatment of common diseases.
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4.
Lipid-sensing nuclear receptors in the pathophysiology and treatment of the metabolic syndrome.
Vacca, M, Degirolamo, C, Mariani-Costantini, R, Palasciano, G, Moschetta, A
Wiley interdisciplinary reviews. Systems biology and medicine. 2011;(5):562-87
Abstract
Metabolic syndrome (MS) is a cluster of different diseases, namely central obesity, hypertension, hyperglycemia, and dyslipidemia, together with a pro-thrombotic and pro-inflammatory state. These metabolic abnormalities are often associated with an increased risk for cardiovascular disease (CVD) and cancer. Dietary and lifestyle modifications are currently believed more effective than pharmacological therapies in the management of MS patients. Nevertheless, the relatively low grade of compliance of patients to these recommendations, as well as the failure of current therapies, highlights the need for the discovery of new pharmacological and nutraceutic approaches. A deeper knowledge of the patho-physiological events that initiate and support the MS is mandatory. Lipid-sensing nuclear receptors (NRs) are the master transcriptional regulators of lipid and carbohydrate metabolism and inflammatory responses, thus standing as suitable targets. This review focuses on the physiological relevance of the NRs (peroxisome proliferator-activated receptors, liver X receptors, and farnesoid X receptor) in the control of whole-body homeostasis, with a special emphasis on lipid and glucose metabolism, and on the relationships between metabolic unbalances, systemic inflammation, and the onset of CVD. Future perspectives and possible clinical applications are also presented.
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5.
PPARs and the complex journey to obesity.
Evans, RM, Barish, GD, Wang, YX
Nature medicine. 2004;(4):355-61
Abstract
Obesity and the related disorders of dyslipidemia and diabetes (components of syndrome X) have become global health epidemics. Over the past decade, the elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metabolism and their intimate link. The three 'lipid-sensing' peroxisome proliferator-activated receptors (PPAR-alpha, PPAR-gamma and PPAR-delta) exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bona fide therapeutic targets. With molecular underpinnings now in place, new pharmacologic approaches to metabolic disease and new questions are emerging.
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6.
Fasting plasma free fatty acid concentrations and Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene in healthy individuals.
Vaccaro, O, Mancini, FP, Ruffa, G, Sabatino, L, Iovine, C, Masulli, M, Colantuoni, V, Riccardi, G
Clinical endocrinology. 2002;(4):481-6
Abstract
BACKGROUND The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma gene has been associated in some, but not all, studies with lower body mass index (BMI) and improved insulin sensitivity; how an altered transcriptional activity of PPARgamma2 could influence insulin sensitivity is currently unclear. The free fatty acids (FFAs) released from adipose tissue triglycerides via lipolysis are key mediators of impaired insulin sensitivity; however, no study has described the relationship of the Pro12Ala mutation with circulating levels of FFAs under physiological conditions. OBJECTIVE To investigate in a population-based sample of Caucasians the relation of the Pro12Ala polymorphism with plasma concentrations of FFAs and other markers of lipid and glucose metabolism described as components of the insulin resistance syndrome. SUBJECTS Four hundred and thirty-eight nondiabetic employees of the Italian Telephone Company, aged 35-65 years, randomly selected from a total population of 3900 participants in a company-sponsored health screening. MEASUREMENTS The Pro12Ala polymorphism of the PPARgamma was studied together with plasma FFAs, insulin, glucose, triglycerides, high density lipoprotein (HDL) cholesterol, blood pressure and anthropometry. The Homeostatic Model Assessment (HOMA) index was calculated as a measure of insulin resistance. RESULTS Carriers and noncarriers of the Pro12Ala polymorphism showed very similar circulating levels of FFA (0.46 +/- 0.2 vs. 0.47 +/- 0.2, NS); plasma glucose, triglycerides, HDL cholesterol and blood pressure were also similar in the two groups with or without the polymorphism. To allow for the possible confounding effect of obesity, a separate analysis was conducted in overweight (BMI > or = 25 kg/m(2)) and normal-weight people (BMI < 25 kg/m(2)). Circulating plasma FFA concentrations, as well as triglycerides, blood pressure and HOMA, were significantly higher in overweight than normal-weight, as expected, but no significant differences were detected between carriers and noncarriers of the Pro12Ala polymorphism within each BMI group (0.49 +/- 0.2 vs. 0.48 +/- 0.2, NS, and 0.44 +/- 0.2 vs. 0.47 +/- 0.2, NS, in overweight and normal-weight, respectively). The Pro12Ala polymorphism was also analysed across increasing quartiles of FFA concentrations and no relationship was observed between the frequency of the polymorphism and FFA values (overall chi2 = 0.48, NS). CONCLUSION This study does not show any relationship between the Pro12Ala polymorphism of the PPARgamma gene and fasting FFAs in the general population. The possibility of a different handling of FFAs under different conditions (i.e. postprandial) cannot be excluded and remains to be explored.
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7.
Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and severe obesity: a case-control study.
Vaccaro, O, Mancini, FP, Ruffa, G, Sabatino, L, Colantuoni, V, Riccardi, G
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 2000;(9):1195-9
Abstract
OBJECTIVE To explore the association of the Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 with severe obesity and the features of the metabolic syndrome in a population-based sample of Caucasians. PARTICIPANTS AND METHODS The study is based on a case-control design: 95 non-diabetic severely obese (body mass index, BMI > 35 kg/m2) cases and 280 normal weight (BMI < 25 kg/m2), age- and sex-matched controls selected from the same population were studied. Height, weight, waist circumference, as well as blood pressure were measured according to a standard protocol. BMI at age 25 y was calculated on the basis of current height and reported weight at age 25 y Biochemical measurements included fasting glucose, triglycerides, high-density lipoprotein cholesterol and insulin. DNA analysis was conducted by PCR and gel electrophoresis. RESULTS Age and gender distribution were similar in obese and normal weight participants. The percentage of people with the Pro12Ala mutation was not significantly different in obese or normal weight participants (20% and 15%, respectively; P = 0.32). Conversely, in obese participants with obesity starting in early adulthood (ie with BMI at age 25 above 26.9kg/m2 which represents the median of the whole obese group), the Pro12Ala mutation was observed significantly more frequently than in the normal weight controls (29% vs 15%; chi square = 4.5, P < 0.05; odds ratio 2.4; 95% CI 1.03-5.36). No association of the Pro12Ala variant with any of the component of the metabolic syndrome measured in the study was observed in either obese, juvenile obese or normal weight participants. CONCLUSIONS Results of this study indicate that the Pro12Ala mutation does not play a major role as a determinant of severe obesity and/or features of the metabolic syndrome in the general population. However, this mutation may be of greater importance as a contributor to early onset obesity.