Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake
Dysregulation of cholesterol homeostasis is associated with various metabolic diseases, including atherosclerosis and type 2 diabetes. The sterol response element binding protein (SREBP)-2 transcription factor induces the expression of genes involved in de novo cholesterol biosynthesis and low densi...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-02-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520350306 |
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| author | Muhua Yang Weidong Liu Christina Pellicane Christine Sahyoun Biny K. Joseph Christina Gallo-Ebert Melissa Donigan Devanshi Pandya Caroline Giordano Adam Bata Joseph T. Nickels, Jr. |
| author_facet | Muhua Yang Weidong Liu Christina Pellicane Christine Sahyoun Biny K. Joseph Christina Gallo-Ebert Melissa Donigan Devanshi Pandya Caroline Giordano Adam Bata Joseph T. Nickels, Jr. |
| author_sort | Muhua Yang |
| collection | DOAJ |
| description | Dysregulation of cholesterol homeostasis is associated with various metabolic diseases, including atherosclerosis and type 2 diabetes. The sterol response element binding protein (SREBP)-2 transcription factor induces the expression of genes involved in de novo cholesterol biosynthesis and low density lipoprotein (LDL) uptake, thus it plays a crucial role in maintaining cholesterol homeostasis. Here, we found that overexpressing microRNA (miR)-185 in HepG2 cells repressed SREBP-2 expression and protein level. miR-185-directed inhibition caused decreased SREBP-2-dependent gene expression, LDL uptake, and HMG-CoA reductase activity. In addition, we found that miR-185 expression was tightly regulated by SREBP-1c, through its binding to a single sterol response element in the miR-185 promoter. Moreover, we found that miR-185 expression levels were elevated in mice fed a high-fat diet, and this increase correlated with an increase in total cholesterol level and a decrease in SREBP-2 expression and protein. Finally, we found that individuals with high cholesterol had a 5-fold increase in serum miR-185 expression compared with control individuals. Thus, miR-185 controls cholesterol homeostasis through regulating SREBP-2 expression and activity. In turn, SREBP-1c regulates miR-185 expression through a complex cholesterol-responsive feedback loop. Thus, a novel axis regulating cholesterol homeostasis exists that exploits miR-185-dependent regulation of SREBP-2 and requires SREBP-1c for function. |
| first_indexed | 2024-12-20T04:17:06Z |
| format | Article |
| id | doaj.art-e8ec46e393164b3f89563e1d830de6fa |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-20T04:17:06Z |
| publishDate | 2014-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-e8ec46e393164b3f89563e1d830de6fa2022-12-21T19:53:44ZengElsevierJournal of Lipid Research0022-22752014-02-01552226238Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptakeMuhua Yang0Weidong Liu1Christina Pellicane2Christine Sahyoun3Biny K. Joseph4Christina Gallo-Ebert5Melissa Donigan6Devanshi Pandya7Caroline Giordano8Adam Bata9Joseph T. Nickels, Jr.10The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691Invivotek, Genesis Biotechnology Group, Hamilton, NJ 08691Invivotek, Genesis Biotechnology Group, Hamilton, NJ 08691To whom correspondence should be addressed; The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691Dysregulation of cholesterol homeostasis is associated with various metabolic diseases, including atherosclerosis and type 2 diabetes. The sterol response element binding protein (SREBP)-2 transcription factor induces the expression of genes involved in de novo cholesterol biosynthesis and low density lipoprotein (LDL) uptake, thus it plays a crucial role in maintaining cholesterol homeostasis. Here, we found that overexpressing microRNA (miR)-185 in HepG2 cells repressed SREBP-2 expression and protein level. miR-185-directed inhibition caused decreased SREBP-2-dependent gene expression, LDL uptake, and HMG-CoA reductase activity. In addition, we found that miR-185 expression was tightly regulated by SREBP-1c, through its binding to a single sterol response element in the miR-185 promoter. Moreover, we found that miR-185 expression levels were elevated in mice fed a high-fat diet, and this increase correlated with an increase in total cholesterol level and a decrease in SREBP-2 expression and protein. Finally, we found that individuals with high cholesterol had a 5-fold increase in serum miR-185 expression compared with control individuals. Thus, miR-185 controls cholesterol homeostasis through regulating SREBP-2 expression and activity. In turn, SREBP-1c regulates miR-185 expression through a complex cholesterol-responsive feedback loop. Thus, a novel axis regulating cholesterol homeostasis exists that exploits miR-185-dependent regulation of SREBP-2 and requires SREBP-1c for function.http://www.sciencedirect.com/science/article/pii/S0022227520350306microRNAmetabolismcholesteroltranscriptionsterol response element binding protein |
| spellingShingle | Muhua Yang Weidong Liu Christina Pellicane Christine Sahyoun Biny K. Joseph Christina Gallo-Ebert Melissa Donigan Devanshi Pandya Caroline Giordano Adam Bata Joseph T. Nickels, Jr. Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake Journal of Lipid Research microRNA metabolism cholesterol transcription sterol response element binding protein |
| title | Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake |
| title_full | Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake |
| title_fullStr | Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake |
| title_full_unstemmed | Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake |
| title_short | Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake |
| title_sort | identification of mir 185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake |
| topic | microRNA metabolism cholesterol transcription sterol response element binding protein |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520350306 |
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