title: Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake.
abstract: 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.
authors.affiliation: The Institute of Metabolic Disorders and Genesis Biotechnology Group, Hamilton, NJ 08691.
authors.forename: Muhua
authors.initials: M
authors.lastname: Yang
authors.forename: Weidong
authors.initials: W
authors.lastname: Liu
authors.forename: Christina
authors.initials: C
authors.lastname: Pellicane
authors.forename: Christine
authors.initials: C
authors.lastname: Sahyoun
authors.forename: Biny K
authors.initials: BK
authors.lastname: Joseph
authors.forename: Christina
authors.initials: C
authors.lastname: Gallo-Ebert
authors.forename: Melissa
authors.initials: M
authors.lastname: Donigan
authors.forename: Devanshi
authors.initials: D
authors.lastname: Pandya
authors.forename: Caroline
authors.initials: C
authors.lastname: Giordano
authors.forename: Adam
authors.initials: A
authors.lastname: Bata
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Nickels
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011973:Receptors, LDL / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D007328:Insulin; C573412:LDLR protein, human; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C552431:MIRN185 microRNA, human; D035683:MicroRNAs; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: cholesterol; metabolism; microRNA; sterol response element binding protein; transcription