Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor‐controlled lipid homeostasis
Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigate...
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| Published in | Hepatology (Baltimore, Md.) Vol. 59; no. 5; pp. 1761 - 1771 |
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| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
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01.05.2014
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| Abstract | Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR‐controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild‐type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1‐dependent manner. Conclusion: Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR‐controlled lipid homeostasis. (Hepatology 2014;59:1761–1771) |
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| AbstractList | Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner.
Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis. Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. Conclusion: Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis. (Hepatology 2014; 59:1761-1771) UNLABELLEDNonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. CONCLUSIONHepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis. Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. Conclusion: Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis. (Hepatology 2014;59:1761-1771) [PUBLICATION ABSTRACT] Non-alcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Over-expression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. Therefore, hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis. |
| Author | Xu, Yang Adorini, Luciano Chen, Wei‐Dong Li, Yuanyuan Yin, Liya Jadhav, Kavita Xu, Jiesi Zhang, Yanqiao Ge, Xuemei |
| AuthorAffiliation | 3 Intercept Pharmaceuticals, 18 Desbrosses Street, New York, NY 10013, USA 1 Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA 2 Key laboratory of receptor-mediated gene regulation and drug discovery, School of Medicine, Henan University, Kaifeng, China |
| AuthorAffiliation_xml | – name: 1 Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA – name: 3 Intercept Pharmaceuticals, 18 Desbrosses Street, New York, NY 10013, USA – name: 2 Key laboratory of receptor-mediated gene regulation and drug discovery, School of Medicine, Henan University, Kaifeng, China |
| Author_xml | – sequence: 1 givenname: Jiesi surname: Xu fullname: Xu, Jiesi organization: Northeast Ohio Medical University – sequence: 2 givenname: Yuanyuan surname: Li fullname: Li, Yuanyuan organization: Northeast Ohio Medical University – sequence: 3 givenname: Wei‐Dong surname: Chen fullname: Chen, Wei‐Dong organization: Henan University – sequence: 4 givenname: Yang surname: Xu fullname: Xu, Yang organization: Northeast Ohio Medical University – sequence: 5 givenname: Liya surname: Yin fullname: Yin, Liya organization: Northeast Ohio Medical University – sequence: 6 givenname: Xuemei surname: Ge fullname: Ge, Xuemei organization: Northeast Ohio Medical University – sequence: 7 givenname: Kavita surname: Jadhav fullname: Jadhav, Kavita organization: Northeast Ohio Medical University – sequence: 8 givenname: Luciano surname: Adorini fullname: Adorini, Luciano organization: Intercept Pharmaceuticals – sequence: 9 givenname: Yanqiao surname: Zhang fullname: Zhang, Yanqiao organization: Northeast Ohio Medical University |
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| Snippet | Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for... UNLABELLEDNonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target... Non-alcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for... |
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| SubjectTerms | Animals Carboxylic Ester Hydrolases - physiology Cholesterol - blood Fatty Acids - metabolism Hepatology Homeostasis Lipid Metabolism Lipids Lipogenesis Liver - enzymology Mice Mice, Inbred C57BL Receptors, Cytoplasmic and Nuclear - physiology Rodents Sterol Regulatory Element Binding Protein 1 - physiology Triglycerides - metabolism |
| Title | Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor‐controlled lipid homeostasis |
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