Human adipocyte differentiation and composition of disease-relevant lipids are regulated by miR-221-3p

MicroRNA-221-3p (miR-221-3p) is associated with both metabolic diseases and cancers. However, its role in terminal adipocyte differentiation and lipid metabolism are uncharacterized. miR-221-3p or its inhibitor was transfected into differentiating or mature human adipocytes. Triglyceride (TG) conten...

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Published in:	Biochimica et biophysica acta. Molecular and cell biology of lipids Vol. 1866; no. 1; p. 158841
Main Authors:	Ahonen, Maria A., Asghar, Muhammad Yasir, Parviainen, Suvi J., Liebisch, Gerhard, Höring, Marcus, Leidenius, Marjut, Fischer-Posovszky, Pamela, Wabitsch, Martin, Mikkola, Tomi S., Törnquist, Kid, Savolainen-Peltonen, Hanna, Haridas, P.A. Nidhina, Olkkonen, Vesa M.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01.01.2021
Subjects:	14-3-3 Proteins - genetics 14-3-3 Proteins - metabolism adipocytes Adipocytes - metabolism Adipocytes - pathology Adipogenesis - genetics Adiponectin - genetics Adiponectin - metabolism Adipose tissue Adipose Tissue - metabolism Adipose Tissue - pathology Adult Aged ATP citrate synthase Breast cancer breast neoplasms Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Case-Control Studies Cell Differentiation Cell Proliferation ceramides Ceramides - classification Ceramides - metabolism Diacylglycerol O-Acyltransferase - genetics Diacylglycerol O-Acyltransferase - metabolism diacylglycerols fas Receptor - genetics fas Receptor - metabolism Fatty Acid-Binding Proteins - genetics Fatty Acid-Binding Proteins - metabolism Female Gene Expression Regulation, Neoplastic Humans Lipase - genetics Lipase - metabolism Lipid Droplets - metabolism Lipid storage Lipogenesis Mammary Glands, Human - metabolism Mammary Glands, Human - pathology MCF-7 Cells microRNA MicroRNAs - agonists MicroRNAs - antagonists & inhibitors MicroRNAs - genetics MicroRNAs - metabolism Middle Aged neoplasm progression Signal Transduction Sphingolipid Sphingolipids - classification Sphingolipids - metabolism sphingomyelins Stearoyl-CoA Desaturase - genetics Stearoyl-CoA Desaturase - metabolism triacylglycerols Triglycerides - classification Triglycerides - metabolism Lipid storage Sphingolipid microRNA Breast cancer Adipose tissue Lipogenesis
ISSN:	1388-1981, 1879-2618, 1879-2618
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Summary:	MicroRNA-221-3p (miR-221-3p) is associated with both metabolic diseases and cancers. However, its role in terminal adipocyte differentiation and lipid metabolism are uncharacterized. miR-221-3p or its inhibitor was transfected into differentiating or mature human adipocytes. Triglyceride (TG) content and adipogenic gene expression were monitored, global lipidome analysis was carried out, and mechanisms underlying the effects of miR-221-3p were investigated. Finally, cross-talk between miR-221-3p expressing adipocytes and MCF-7 breast carcinoma (BC) cells was studied, and miR-221-3p expression in tumor-proximal adipose biopsies from BC patients analyzed. miR-221-3p overexpression inhibited terminal differentiation of adipocytes, as judged from reduced TG storage and gene expression of the adipogenic markers SCD1, GLUT4, FAS, DGAT1/2, AP2, ATGL and AdipoQ, whereas the miR-221-3p inhibitor increased TG storage. Knockdown of the predicted miR-221-3p target, 14-3-3γ, had similar antiadipogenic effects as miR-221-3p overexpression, indicating it as a potential mediator of mir-221-3p function. Importantly, miR-221-3p overexpression inhibited de novo lipogenesis but increased the concentrations of ceramides and sphingomyelins, while reducing diacylglycerols, concomitant with suppression of sphingomyelin phosphodiesterase, ATP citrate lyase, and acid ceramidase. miR-221-3p expression was elevated in tumor proximal adipose tissue from patients with invasive BC. Conditioned medium of miR-221-3p overexpressing adipocytes stimulated the invasion and proliferation of BC cells, while medium of the BC cells enhanced miR-221-3p expression in adipocytes. Elevated miR-221-3p impairs adipocyte lipid storage and differentiation, and modifies their ceramide, sphingomyelin, and diacylglycerol content. These alterations are relevant for metabolic diseases but may also affect cancer progression. •miR-221-3p suppresses adipogenesis, putatively mediated by 14-3-3γ downregulation.•miR-221-3p suppresses de novo lipogenesis in adipocytes.•miR-221-3p alters adipocyte ceramide, sphingomyelin and diacylglycerol content.•miR-221-3p expression is elevated in adipocytes adjacent to breast carcinoma.•Adipocyte miR-221-3p elevation may promote metabolic disease and cancer progression.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1388-1981 1879-2618 1879-2618
DOI:	10.1016/j.bbalip.2020.158841