•The components of the metabolic syndrome are associated with reduced levels of beneficial bacteria in the gut microflora.•Prebiotics promote the growth of beneficial bacteria in the gut, which and ...could have protective effects on metabolic health.•Prebiotic supplementation could improve metabolic syndrome components in individuals with type 2 diabetes.•Data from healthy individuals or from those with the metabolic syndrome show discrepancies.•More clinical trials are needed to set recommendations on the use of prebiotics.
Components of the metabolic syndrome (MetS), including abdominal obesity, low-grade chronic systemic inflammation, altered glucose metabolism, dyslipidemia and high blood pressure, are major threats to healthy aging in modern societies. The connection between MetS components and gut microflora is now acknowledged and multiple therapeutic strategies have been proposed to change the composition of the gut microbiota in order to promote optimal metabolic health. Prebiotics have the ability to favour growth of beneficial bacteria, especially short-chain fatty-acids (SCFA) producers. Increased SCFA in the gut is associated with improved satiety and weight loss, reduced systemic inflammation by increasing the gut barrier function, and improved glucose and lipid metabolism. The objective of this review is to examine the recent literature in order to determine the types and doses of prebiotics that could be recommended for the management of MetS. A review of the literature was executed using the MEDLINE database and clinical trials from 2013 to 2017 were selected for analysis. In conclusion, a daily supplementation of 10g of inulin, resistant starches or fructo-oligosaccharide-enriched inulin could have beneficial effects on MetS components in individuals with type 2 diabetes. In healthy subjects or in individuals with the MetS, the results are too heterogeneous and scarce to be able to set any specific recommendations. More clinical studies are needed to better understand the role of prebiotics in the management of MetS components.
Uridine diphosphate-glucuronosyltransferase 2 (UGT2)B15 and B17 enzymes conjugate dihydrotestosterone (DHT) and its metabolites androstane-3α, 17β-diol (3α-DIOL) and androsterone (ADT). The presence ...of UGT2B15/B17 in the epithelial cells of the human prostate has been clearly demonstrated, and significant 3α-DIOL glucuronide and ADT-glucuronide concentrations have been detected in this tissue. The human androgen-dependent cancer cell line, LNCaP, expresses UGT2B15 and -B17 and is also capable of conjugating androgens. To assess the impact of these two genes in the inactivation of androgens in LNCaP cells, their expression was inhibited using RNA interference. The efficient inhibitory effects of a UGT2B15/B17 small interfering RNA (siRNA) probe was established by the 70% reduction of these UGT mRNA levels, which was further confirmed at the protein levels. The glucuronidation of dihydrotestosterone (DHT), 3α-DIOL, and ADT by LNCaP cell homogenates was reduced by more than 75% in UGT2B15/B17 siRNA-transfected LNCaP cells when compared with cells transfected with a non-target probe. In UGT2B15/B17-deficient LNCaP cells, we observe a stronger response to DHT than in control cells, as determined by cell proliferation and expression of eight known androgen-sensitive genes. As expected, the amounts of DHT in cell culture media from control cells were significantly lower than that from UGT2B15/B17 siRNA-treated cells, which was caused by a higher conversion to its corresponding glucuronide derivative. Taken together these data support the idea that UGT2B15 and -B17 are critical enzymes for the local inactivation of androgens and that glucuronidation is a major determinant of androgen action in prostate cells.
Glucuronidation, catalyzed by UDP-glucuronosyltransferase UGT2B enzymes, is a major inactivating and elimination pathway for androgen hormones in humans. Whether Ugt2b enzymes from mice are also ...reactive with these hormones have never been investigated. The present study aimed at evaluating the capability of murine tissues and Ugt2b enzymes to glucuronidated androgens. The 7 murine Ugt2b (Ugt2b1, 2b5, 2b34, 2b35, 2b36, 2b37 and 2b38) enzymes were cloned and stably expressed into HEK293 cells. In vitro glucuronidation assays were performed with microsomal proteins or homogenates from mice tissues (liver, kidney, intestine, adipose, testis, prostate, epididymis, bulbo, seminal vesicle, mammary glands, uterus, and ovary) and from Ugt2b-HEK293 cells. Male and female livers, as well as male kidneys, are the major sites for androgen glucuronidation in mice. The male liver is highly efficient at glucuronidation of dihydrotestosterone (DHT) and testosterone and is enriched in Ugt2b1 and 2b5 enzymes. Androsterone and 3α-Diol are conjugated in the male kidney through an Ugt2b37-dependent process. Interestingly, castration partially abolished hepatic Ugt2b1 expression and activity, while Ugt2b37 was totally repressed. DHT injection partially corrected these changes. In conclusion, these observations revealed the substrate- and tissue-specific manner in which murine Ugt2b enzymes conjugate androgens. They also evidence how androgens modulate their own glucuronide conjugation in mice.
In humans, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD and 5α-reductase activities in androgen target tissues, such as the prostate and skin, convert dehydroepiandrosterone, androstenedione and ...testosterone into the most potent natural androgen dihydrotestosterone (DHT). This androgen is converted mainly
in situ into two phase I metabolites, androsterone (ADT) and androstane-3α,17β-diol (3α-DIOL), which might be back converted to DHT. Here, we discuss the recent findings regarding the characterization of specific UDP-glucuronosyltransferases (UGTs), UGT2B7, B15 and B17, responsible for the glucuronidation of these metabolites. The tissue distribution and cellular localization of the UGT2B transcripts and proteins in humans clearly indicate that these enzymes are synthesized in androgen-sensitive tissues. It is postulated that the conjugating activity of UGT enzymes is the main mechanism for modulating the action of steroids and protecting the androgen-sensitive tissues from deleteriously high concentrations of DHT, ADT and 3α-DIOL.
The 9 UDP-glucuronosyltranferases (UGTs) encoded by the UGT1 locus in humans are key enzymes in the metabolism of most drugs as well as endogenous substances such as bile acids, fatty acids, ...steroids, hormones, neurotransmitters, and bilirubin. Severe unconjugated hyperbilirubinemia in humans that suffer from Crigler-Najjar type I disease results from lesions in the UGT1A1 gene and is often fatal. To examine the physiological importance of the Ugt1 locus in mice, this locus was rendered non-functional by interrupting exon 4 to create Ugt1-/- mice. Because UGT1A1 in humans is responsible for 100% of the conjugated bilirubin, it followed that newborn Ugt1-/- mice developed serum levels of unconjugated bilirubin that were 40-60 times higher than Ugt1+/- or wild-type mice. The result of extreme unconjugated bilirubin in Ugt1-/- mice, comparable to the induced levels noted in patients with Crigler-Najjar type 1 disease, is fatal in neonatal Ugt1-/- mice within 2 weeks following birth. The extreme jaundice is present as a phenotype in skin color after 8 h. Neonatal Ugt1-/- mice exhibit no detectable UGT1A-specific RNA, which corresponds to a complete absence of UGT1A proteins in liver microsomes. Conserved glucuronidation activity attributed to the Ugt1 locus can be defined in Ugt1-/- mice, because UGT2-dependent glucuronidation activity is unaffected. Remarkably, the loss of UGT1A functionality in liver results in significant alterations in cellular metabolism as investigated through changes in gene expression. Thus, the loss of UGT1A function in Ugt1-/- mice leads to a metabolic syndrome that can serve as a model to further investigate the toxicities associated with unconjugated bilirubin and the impact of this disease in humans.
Conjugation by UDP-Glucuronosyltransferase (UGT) is the major pathway of androgen metabolism and elimination in the human. High concentrations of glucuronide conjugates of androsterone (ADT) and ...androstane-3α,17β-diol (3α-diol) are present in circulation and several studies over the last 30 years have concluded that the serum levels of these metabolites might reflect the androgen metabolism in several tissues, including the liver and androgen target tissues. Three UGT2B enzymes are responsible for the conjugation of DHT and its metabolites ADT and 3α-diol: UGT2B7, B15 and B17. UGT2B7 is expressed in the liver and skin whereas UGT2B15 and B17 were found in the liver, prostate and skin. Very specific antibodies against each UGT2B enzyme have been obtained and used for immunohistochemical studies in the human prostate. It was shown that UGT2B17 is expressed in basal cells whereas UGT2B15 is only localized in luminal cells, where it inactivates DHT. By using LNCaP cells, we have also demonstrated that the expression and activity of UGT2B15 and B17 are modulated by several endogenous prostate factors including androgen. Finally, to study the physiological role of UGT2B enzymes, transgenic mice bearing the human UGT2B15 gene were recently obtained. A decrease in reproductive tissue weight from transgenic animals compared to those from control animals was observed. In conclusion, the conjugation by UGT2B7, B15 and B17, which represents a non-reversible step in androgen metabolism, is an important means by which androgens are regulated locally. It is also postulated that UGT enzymes protect the tissue from deleteriously high concentrations of active androgen.
Androgens as well as monohydroxy-fatty acids are implicated in the pathogenesis of prostate cancer. Like a huge variety of endo- and xenobiotics, they are eliminated as glucuronide conjugates formed ...by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. In the present study, we observe that treatment of the prostate cancer cells LNCaP with natural and synthetic androgens, IL-1α, or epidermal growth factor (EGF) differently modulates the glucuronidation of androgen and bioactive lipid metabolites. Indeed, glucuronidation of 5α-androstane-3α,17β-diol and 13-hydroxyoctadecadienoic acid was drastically reduced, whereas 12-hydroxyeicosatetraenoic acid conjugation by UGT was increased after androgen treatment. These effects reflected the reduction of UGT2B10, -B15, and -B17 enzyme expression, and the activation of the UGT2B11 gene. In human prostate epithelial cells, only UGT2B11 and -B15 mRNAs are detected and are regulated by androgens in a similar manner as in LNCaP cells. In LNCaP cells, IL-1α and EGF also regulate UGT2B expression in an isoform-specific manner; IL-1α induced UGT2B10 and reduced UGT2B17, while having no effects on UGT2B11 mRNA levels. EGF treatment resulted in a decreased UGT2B17 expression, whereas UGT2B10 and -B11 mRNA remained at their basal levels. Overall, these results demonstrate that in the human prostate, androgens do not only affect their own inactivation but also influence the levels of monohydroxy-fatty acids by regulating the expression of UGT2B enzymes in an isoform-specific manner. These differential effects of androgens, IL-1α, and EGF on lipid metabolism likely constitute an additional mechanism by which these endogenous factors promote prostate cancer development.
Androgens are major regulators of prostate cell growth and physiology. In the human prostate, androgens are inactivated in the form of hydrophilic glucuronide conjugates. These metabolites are formed ...by the two human UGT2B15 UGT (UDP-glucuronosyltransferase) 2B15 and UGT2B17 enzymes. The FXR (farnesoid X receptor) is a bile acid sensor controlling hepatic and/or intestinal cholesterol, lipid and glucose metabolism. In the present study, we report the expression of FXR in normal and cancer prostate epithelial cells, and we demonstrate that its activation by chenodeoxycholic acid or GW4064 negatively interferes with the levels of UGT2B15 and UGT2B17 mRNA and protein in prostate cancer LNCaP cells. FXR activation also causes a drastic reduction of androgen glucuronidation in these cells. These results point out activators of FXR as negative regulators of androgen-conjugating UGT expression in the prostate. Finally, the androgen metabolite androsterone, which is also an activator of FXR, dose-dependently reduces the glucuronidation of androgens catalysed by UGT2B15 and UGT2B17 in an FXR-dependent manner in LNCaP cells. In conclusion, the present study identifies for the first time the activators of FXR as important regulators of androgen metabolism in human prostate cancer cells.
Arachidonic acids (AA) and linoleic acids (LAs) are metabolized, in several tissues, to hydroxylated metabolites that are important mediators of many physiological and pathophysiological processes. ...The conjugation of leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (HETE), 12-HETE, 15-HETE, and 13-hydroxyoctadecadienoic acid (HODE) by the human UDP-glucuronosyltransferase (UGT) enzymes was investigated. All substrates tested were efficiently conjugated by human liver microsomes to polar derivatives containing the glucuronyl moiety as assessed by mass spectrometry. The screening analyses with stably expressed UGT enzymes in HK293 showed that glucuronidation of LTB4 was observed with UGT1A1, UGT1A3, UGT1A8, and UGT2B7, whereas UGT1A1, UGT1A3, UGT1A4, and UGT1A9 also conjugated most of the HETEs and 13-HODE. LA and AA metabolites also appear to be good substrates for the UGT2B subfamily members, especially for UGT2B4 and UGT2B7 that conjugate all HETE and 13-HODE. Interestingly, UGT2B10 and UGT2B11, which are considered as orphan enzymes since no conjugation activity has so far been demonstrated with these enzymes, conjugated 12-HETE, 15-HETE, and 13-HODE. In summary, our data showed that several members of UGT1A and UGT2B families are capable of converting LA and AA metabolites into glucuronide derivatives, which is considered an irreversible step to inactivation and elimination of endogenous substances from the body.
Fulvestrant (Faslodex) is administered by intramuscular injection and is converted into ketone, sulfate, sulfone and glucuronide metabolites. Glucuronidation, catalyzed by 18 members of the ...UDP-glucuronosyltransferase (UGT) enzyme family, plays a major role in the elimination of natural estrogens. The present study was aimed at identifying and characterizing human UGT enzymes involved in the glucuronidation of this antiestrogen as well as other synthetic estrogen derivatives with aliphatic chains on the E2 molecule. In contrast to E2, which is conjugated by UGT1A1, -1A3, -1A8, -1A10, and -2B7, fulvestrant is glucuronidated by UGT1A1, -1A3, -1A4, and -1A8. The four UGT1A-fulvestrant conjugating enzymes glucuronidate this substrate at position 3, whereas only UGT1A8 also produces fulvestrant-17-glucuronide. For E2, only UGT1A3 and UGT2B7 are capable to conjugate at 17-hydroxyposition. These observations indicate that addition of an aliphatic chain to the E2 molecule modifies the specificity of the UGT enzymes toward the C18 molecules. To further investigate the specificity of these enzymes, a series of E2 derivatives with aliphatic or phenyl chains at position 2, 7alpha, and 11beta was also tested for its conjugation with human UGT enzymes. It was observed that, in addition to UGT1A3, UGT1A1 and UGT1A8 also played important roles for the glucuronidation of these compounds. This suggests that the basic structure of E2 is one of the major determinants for the glucuronidation catalyzed by this group of enzymes. Considering the high level of UGT1A3 and -1A4 expression in the gastrointestinal tract and mammary gland, our results suggest that fulvestrant can be inactivated both in intestine and in its target tissue.
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