1.
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).
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.
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.
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.