The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice
Purpose: Bile acids (BAs) have been shown to contribute to glucose and energy homeostasis. We have recently reported that miglitol, an alpha-glucosidase inhibitor, increases fecal BA excretion and ameliorate insulin resistance and obesity in mice. The aim of this study was to clarify the mechanisms...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | Metabolism Open |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589936820300049 |
| _version_ | 1828940860853583872 |
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| author | Yoji Hamada Moritaka Goto Go Nishimura Hiroshi Nagasaki Yusuke Seino Hideki Kamiya Jiro Nakamura |
| author_facet | Yoji Hamada Moritaka Goto Go Nishimura Hiroshi Nagasaki Yusuke Seino Hideki Kamiya Jiro Nakamura |
| author_sort | Yoji Hamada |
| collection | DOAJ |
| description | Purpose: Bile acids (BAs) have been shown to contribute to glucose and energy homeostasis. We have recently reported that miglitol, an alpha-glucosidase inhibitor, increases fecal BA excretion and ameliorate insulin resistance and obesity in mice. The aim of this study was to clarify the mechanisms by which miglitol affects BA metabolism. The expression of genes regulating BA metabolism, gut microbiome and short-chain fatty acids (SCFA) were examined. Procedures: NSY mice, representing an obese type 2 diabetic model, were fed with a high-fat diet with or without miglitol for 4 weeks. The expression of BA-related genes in the liver and the lower intestine were measured. Alterations in fecal microbiome, fecal SCFA along with plasma lipid levels were also evaluated. Major findings: Miglitol significantly increased fecal BA secretion and markedly upregulated the mRNA expression, protein levels and enzyme activity of hepatic cholesterol 7α-hydroxylase, a rate-limiting enzyme of BA synthesis. In the intestine, miglitol treatment significantly suppressed the mRNA expression of apical sodium-dependent bile acid transporter and ATP-binding cassette transporter G5 and G8. In fecal microbiome, the prevalence of prevotella was remarkably reduced and that of clostridium subcluster XIVa was increased by miglitol. Miglitol elevated formic and n-butyric acids along with total SCFA concentration in feces, while succinic acid was decreased. There was no change in plasma total cholesterol levels. Conclusions: Collectively, miglitol may affect BA metabolism via enhanced CYP7A1 activity resulting from at least in part the alterations in gut microbiome and SCFA production in obese diabetic mice. Keywords: Alpha-glucosidase inhibitors, Bile acids, Cholesterol 7α-hydroxylase, Gut microbiome, Short-chain fatty acids, Miglitol |
| first_indexed | 2024-12-14T03:27:28Z |
| format | Article |
| id | doaj.art-de43ff0d85ac40d8ab1113166f6ed2f9 |
| institution | Directory Open Access Journal |
| issn | 2589-9368 |
| language | English |
| last_indexed | 2024-12-14T03:27:28Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Metabolism Open |
| spelling | doaj.art-de43ff0d85ac40d8ab1113166f6ed2f92022-12-21T23:18:51ZengElsevierMetabolism Open2589-93682020-03-015The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic miceYoji Hamada0Moritaka Goto1Go Nishimura2Hiroshi Nagasaki3Yusuke Seino4Hideki Kamiya5Jiro Nakamura6Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan; Corresponding author. Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, 480-1195, Japan.Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co, Ltd, 363 Shiozaki, Hokusei-cho, Inabe, 511-0406, JapanPharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co, Ltd, 363 Shiozaki, Hokusei-cho, Inabe, 511-0406, JapanDepartment of Physiology I, Fujita University School of Medicine, 1-98 Kutsukake-cho, Toyoake, Aichi, 470-1192, JapanDepartment of Endocrinology and Diabetes, Fujita University School of Medicine, 1-98 Kutsukake-cho, Toyoake, Aichi, 470-1192, JapanDivision of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, JapanDivision of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, JapanPurpose: Bile acids (BAs) have been shown to contribute to glucose and energy homeostasis. We have recently reported that miglitol, an alpha-glucosidase inhibitor, increases fecal BA excretion and ameliorate insulin resistance and obesity in mice. The aim of this study was to clarify the mechanisms by which miglitol affects BA metabolism. The expression of genes regulating BA metabolism, gut microbiome and short-chain fatty acids (SCFA) were examined. Procedures: NSY mice, representing an obese type 2 diabetic model, were fed with a high-fat diet with or without miglitol for 4 weeks. The expression of BA-related genes in the liver and the lower intestine were measured. Alterations in fecal microbiome, fecal SCFA along with plasma lipid levels were also evaluated. Major findings: Miglitol significantly increased fecal BA secretion and markedly upregulated the mRNA expression, protein levels and enzyme activity of hepatic cholesterol 7α-hydroxylase, a rate-limiting enzyme of BA synthesis. In the intestine, miglitol treatment significantly suppressed the mRNA expression of apical sodium-dependent bile acid transporter and ATP-binding cassette transporter G5 and G8. In fecal microbiome, the prevalence of prevotella was remarkably reduced and that of clostridium subcluster XIVa was increased by miglitol. Miglitol elevated formic and n-butyric acids along with total SCFA concentration in feces, while succinic acid was decreased. There was no change in plasma total cholesterol levels. Conclusions: Collectively, miglitol may affect BA metabolism via enhanced CYP7A1 activity resulting from at least in part the alterations in gut microbiome and SCFA production in obese diabetic mice. Keywords: Alpha-glucosidase inhibitors, Bile acids, Cholesterol 7α-hydroxylase, Gut microbiome, Short-chain fatty acids, Miglitolhttp://www.sciencedirect.com/science/article/pii/S2589936820300049 |
| spellingShingle | Yoji Hamada Moritaka Goto Go Nishimura Hiroshi Nagasaki Yusuke Seino Hideki Kamiya Jiro Nakamura The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice Metabolism Open |
| title | The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice |
| title_full | The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice |
| title_fullStr | The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice |
| title_full_unstemmed | The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice |
| title_short | The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice |
| title_sort | alpha glucosidase inhibitor miglitol increases hepatic cyp7a1 activity in association with altered short chain fatty acid production in the gut of obese diabetic mice |
| url | http://www.sciencedirect.com/science/article/pii/S2589936820300049 |
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