Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice[S]
Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepat...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-10-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520353013 |
| _version_ | 1818740420069294080 |
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| author | Lipeng Bi John Y.L. Chiang Wen-Xing Ding Winston Dunn Benjamin Roberts Tiangang Li |
| author_facet | Lipeng Bi John Y.L. Chiang Wen-Xing Ding Winston Dunn Benjamin Roberts Tiangang Li |
| author_sort | Lipeng Bi |
| collection | DOAJ |
| description | Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Elevated circulating free fatty acids play key roles in hepatic VLDL overproduction and the development of dyslipidemia. This study investigated the regulation of hepatic Sort1 in obesity and diabetes and the potential implications in diabetic dyslipidemia. Results showed that hepatic Sort1 protein was markedly decreased in mouse models of type I and type II diabetes and in human individuals with obesity and liver steatosis, whereas increasing hepatic Sort1 expression reduced plasma cholesterol and triglycerides in mice. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation. Consistently, hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort1 protein in mice. These results suggest that increased saturated fatty acids downregulate liver Sort1 protein, which may contribute to the development of dyslipidemia in obesity and diabetes. |
| first_indexed | 2024-12-18T01:40:26Z |
| format | Article |
| id | doaj.art-abd0adc6911d46599089273fce2b7a6f |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-18T01:40:26Z |
| publishDate | 2013-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-abd0adc6911d46599089273fce2b7a6f2022-12-21T21:25:21ZengElsevierJournal of Lipid Research0022-22752013-10-01541027542762Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice[S]Lipeng Bi0John Y.L. Chiang1Wen-Xing Ding2Winston Dunn3Benjamin Roberts4Tiangang Li5Department of Pharmacology, Toxicology, and Therapeutics and Liver Center, University of Kansas Medical Center, Kansas City, KS 66160; andDepartment of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272Department of Pharmacology, Toxicology, and Therapeutics and Liver Center, University of Kansas Medical Center, Kansas City, KS 66160; andDepartment of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160; andDepartment of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160; andTo whom correspondence should be addressed; Department of Pharmacology, Toxicology, and Therapeutics and Liver Center, University of Kansas Medical Center, Kansas City, KS 66160; andHepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Elevated circulating free fatty acids play key roles in hepatic VLDL overproduction and the development of dyslipidemia. This study investigated the regulation of hepatic Sort1 in obesity and diabetes and the potential implications in diabetic dyslipidemia. Results showed that hepatic Sort1 protein was markedly decreased in mouse models of type I and type II diabetes and in human individuals with obesity and liver steatosis, whereas increasing hepatic Sort1 expression reduced plasma cholesterol and triglycerides in mice. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation. Consistently, hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort1 protein in mice. These results suggest that increased saturated fatty acids downregulate liver Sort1 protein, which may contribute to the development of dyslipidemia in obesity and diabetes.http://www.sciencedirect.com/science/article/pii/S0022227520353013extracellular signal-regulated kinaseobesitydiabetesfatty liverlipid metabolismmitogen-activated protein kinase |
| spellingShingle | Lipeng Bi John Y.L. Chiang Wen-Xing Ding Winston Dunn Benjamin Roberts Tiangang Li Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice[S] Journal of Lipid Research extracellular signal-regulated kinase obesity diabetes fatty liver lipid metabolism mitogen-activated protein kinase |
| title | Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice[S] |
| title_full | Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice[S] |
| title_fullStr | Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice[S] |
| title_full_unstemmed | Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice[S] |
| title_short | Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice[S] |
| title_sort | saturated fatty acids activate erk signaling to downregulate hepatic sortilin 1 in obese and diabetic mice s |
| topic | extracellular signal-regulated kinase obesity diabetes fatty liver lipid metabolism mitogen-activated protein kinase |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520353013 |
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