miRNA-218 targets lipin-1 and glucose transporter type 4 genes in 3T3-L1 cells treated with lopinavir/ritonavir

Elena Bresciani, Cecilia Saletti, Nicola Squillace, Laura Rizzi, Laura Molteni, Ramona Meanti, Robert J. Omeljaniuk, Giuseppe Biagini, Andrea Gori, Vittorio Locatelli, Antonio Torsello

Research output: Contribution to journalArticle

Abstract

Background: Metabolic complications represent a common and serious problem associated with HIV infection and combined Antiretroviral Therapy (cART). Alterations in body fat distribution are associated with significantly increased risks of (i) metabolic derangements, (ii) cardiovascular pathologies, and (iii) insulin resistance. A case control study showed that in subcutaneous adipose tissue from HIV-infected patients on cART presenting lipodystrophy (LS), the levels of miRNA-218 were upregulated and those of lipin-1, a putative target gene of miRNA-218, were downregulated compared with HIV-negative subjects. Lipin-1 is one of the most important factors linked to development of LS. Lipin-1, by controlling PPARγ2, regulates the expression of specific genes, such as that of glucose transporter type 4 (GLUT-4), required for maturation and maintenance of adipocytes. Objectives: To determine whether lopinavir/ritonavir (LPV/RTV) can modulate lipogenesis in adipocytes affecting miRNA-218 and lipin-1 mRNA expression, and to investigate the functional link between miRNA-218 and GLUT-4 mRNA expression. Methods: Differentiated 3T3-L1 cells were treated with various combinations of LPV/RTV, followed by measurements of cell viability, lipid accumulation, lipin-1 and GLUT-4 mRNA and miRNA-218 levels. Transfection of anti-miR-218 or a miRNA-218 mimic were used to investigate the role of miRNA-218 in lipogenesis. Results: LPV/RTV treatment of 3T3-L1 cells did not affect the viability of differentiated 3T3-L1 cells, but caused (i) a significant decrease of lipid accumulation, (ii) an overexpression of miRNA-218, and (iii) a reduction of lipin-1 and GLUT-4 mRNA levels. The anti-miR-218 transfection of 3T3-L1 cells significantly ameliorated the adipogenic dysfunction and restored mRNA levels of lipin-1 and GLUT-4 consequent to LPV/RTV treatment. By contrast, 3T3-L1 cells transfected with a specific miRNA-218 mimic showed (i) an overexpression of miRNA-218, (ii) a reduced cellular lipid fraction, and (iii) decreased levels of mRNA for lipin-1 and GLUT-4. Conclusion: 3T3-L1 cells, treated with LPV/RTV, show altered lipid content due to increased miRNA-218 levels, which affects lipin-1 mRNA. Moreover, increased miRNA-218 levels were inversely correlated with changes in GLUT-4 expression, which suggests a role for miRNA-218 in mediating the insulin resistance consequent to cART.

Original languageEnglish
Article number461
JournalFrontiers in Pharmacology
Volume10
Issue numberAPR
DOIs
Publication statusPublished - Jan 1 2019

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Glucose Transporter Type 4
Lopinavir
3T3-L1 Cells
Ritonavir
MicroRNAs
Genes
Messenger RNA
Lipodystrophy
Lipids
Lipogenesis
Adipocytes
lipine
Transfection
Insulin Resistance
HIV
Body Fat Distribution
Subcutaneous Fat
Therapeutics

Keywords

  • Adipocyte
  • HIV protease inhibitors
  • Insulin resistance
  • Lipodystrophy
  • MiRNA

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Bresciani, E., Saletti, C., Squillace, N., Rizzi, L., Molteni, L., Meanti, R., ... Torsello, A. (2019). miRNA-218 targets lipin-1 and glucose transporter type 4 genes in 3T3-L1 cells treated with lopinavir/ritonavir. Frontiers in Pharmacology, 10(APR), [461]. https://doi.org/10.3389/fphar.2019.00461

miRNA-218 targets lipin-1 and glucose transporter type 4 genes in 3T3-L1 cells treated with lopinavir/ritonavir. / Bresciani, Elena; Saletti, Cecilia; Squillace, Nicola; Rizzi, Laura; Molteni, Laura; Meanti, Ramona; Omeljaniuk, Robert J.; Biagini, Giuseppe; Gori, Andrea; Locatelli, Vittorio; Torsello, Antonio.

In: Frontiers in Pharmacology, Vol. 10, No. APR, 461, 01.01.2019.

Research output: Contribution to journalArticle

Bresciani, E, Saletti, C, Squillace, N, Rizzi, L, Molteni, L, Meanti, R, Omeljaniuk, RJ, Biagini, G, Gori, A, Locatelli, V & Torsello, A 2019, 'miRNA-218 targets lipin-1 and glucose transporter type 4 genes in 3T3-L1 cells treated with lopinavir/ritonavir', Frontiers in Pharmacology, vol. 10, no. APR, 461. https://doi.org/10.3389/fphar.2019.00461
Bresciani, Elena ; Saletti, Cecilia ; Squillace, Nicola ; Rizzi, Laura ; Molteni, Laura ; Meanti, Ramona ; Omeljaniuk, Robert J. ; Biagini, Giuseppe ; Gori, Andrea ; Locatelli, Vittorio ; Torsello, Antonio. / miRNA-218 targets lipin-1 and glucose transporter type 4 genes in 3T3-L1 cells treated with lopinavir/ritonavir. In: Frontiers in Pharmacology. 2019 ; Vol. 10, No. APR.
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abstract = "Background: Metabolic complications represent a common and serious problem associated with HIV infection and combined Antiretroviral Therapy (cART). Alterations in body fat distribution are associated with significantly increased risks of (i) metabolic derangements, (ii) cardiovascular pathologies, and (iii) insulin resistance. A case control study showed that in subcutaneous adipose tissue from HIV-infected patients on cART presenting lipodystrophy (LS), the levels of miRNA-218 were upregulated and those of lipin-1, a putative target gene of miRNA-218, were downregulated compared with HIV-negative subjects. Lipin-1 is one of the most important factors linked to development of LS. Lipin-1, by controlling PPARγ2, regulates the expression of specific genes, such as that of glucose transporter type 4 (GLUT-4), required for maturation and maintenance of adipocytes. Objectives: To determine whether lopinavir/ritonavir (LPV/RTV) can modulate lipogenesis in adipocytes affecting miRNA-218 and lipin-1 mRNA expression, and to investigate the functional link between miRNA-218 and GLUT-4 mRNA expression. Methods: Differentiated 3T3-L1 cells were treated with various combinations of LPV/RTV, followed by measurements of cell viability, lipid accumulation, lipin-1 and GLUT-4 mRNA and miRNA-218 levels. Transfection of anti-miR-218 or a miRNA-218 mimic were used to investigate the role of miRNA-218 in lipogenesis. Results: LPV/RTV treatment of 3T3-L1 cells did not affect the viability of differentiated 3T3-L1 cells, but caused (i) a significant decrease of lipid accumulation, (ii) an overexpression of miRNA-218, and (iii) a reduction of lipin-1 and GLUT-4 mRNA levels. The anti-miR-218 transfection of 3T3-L1 cells significantly ameliorated the adipogenic dysfunction and restored mRNA levels of lipin-1 and GLUT-4 consequent to LPV/RTV treatment. By contrast, 3T3-L1 cells transfected with a specific miRNA-218 mimic showed (i) an overexpression of miRNA-218, (ii) a reduced cellular lipid fraction, and (iii) decreased levels of mRNA for lipin-1 and GLUT-4. Conclusion: 3T3-L1 cells, treated with LPV/RTV, show altered lipid content due to increased miRNA-218 levels, which affects lipin-1 mRNA. Moreover, increased miRNA-218 levels were inversely correlated with changes in GLUT-4 expression, which suggests a role for miRNA-218 in mediating the insulin resistance consequent to cART.",
keywords = "Adipocyte, HIV protease inhibitors, Insulin resistance, Lipodystrophy, MiRNA",
author = "Elena Bresciani and Cecilia Saletti and Nicola Squillace and Laura Rizzi and Laura Molteni and Ramona Meanti and Omeljaniuk, {Robert J.} and Giuseppe Biagini and Andrea Gori and Vittorio Locatelli and Antonio Torsello",
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T1 - miRNA-218 targets lipin-1 and glucose transporter type 4 genes in 3T3-L1 cells treated with lopinavir/ritonavir

AU - Bresciani, Elena

AU - Saletti, Cecilia

AU - Squillace, Nicola

AU - Rizzi, Laura

AU - Molteni, Laura

AU - Meanti, Ramona

AU - Omeljaniuk, Robert J.

AU - Biagini, Giuseppe

AU - Gori, Andrea

AU - Locatelli, Vittorio

AU - Torsello, Antonio

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Metabolic complications represent a common and serious problem associated with HIV infection and combined Antiretroviral Therapy (cART). Alterations in body fat distribution are associated with significantly increased risks of (i) metabolic derangements, (ii) cardiovascular pathologies, and (iii) insulin resistance. A case control study showed that in subcutaneous adipose tissue from HIV-infected patients on cART presenting lipodystrophy (LS), the levels of miRNA-218 were upregulated and those of lipin-1, a putative target gene of miRNA-218, were downregulated compared with HIV-negative subjects. Lipin-1 is one of the most important factors linked to development of LS. Lipin-1, by controlling PPARγ2, regulates the expression of specific genes, such as that of glucose transporter type 4 (GLUT-4), required for maturation and maintenance of adipocytes. Objectives: To determine whether lopinavir/ritonavir (LPV/RTV) can modulate lipogenesis in adipocytes affecting miRNA-218 and lipin-1 mRNA expression, and to investigate the functional link between miRNA-218 and GLUT-4 mRNA expression. Methods: Differentiated 3T3-L1 cells were treated with various combinations of LPV/RTV, followed by measurements of cell viability, lipid accumulation, lipin-1 and GLUT-4 mRNA and miRNA-218 levels. Transfection of anti-miR-218 or a miRNA-218 mimic were used to investigate the role of miRNA-218 in lipogenesis. Results: LPV/RTV treatment of 3T3-L1 cells did not affect the viability of differentiated 3T3-L1 cells, but caused (i) a significant decrease of lipid accumulation, (ii) an overexpression of miRNA-218, and (iii) a reduction of lipin-1 and GLUT-4 mRNA levels. The anti-miR-218 transfection of 3T3-L1 cells significantly ameliorated the adipogenic dysfunction and restored mRNA levels of lipin-1 and GLUT-4 consequent to LPV/RTV treatment. By contrast, 3T3-L1 cells transfected with a specific miRNA-218 mimic showed (i) an overexpression of miRNA-218, (ii) a reduced cellular lipid fraction, and (iii) decreased levels of mRNA for lipin-1 and GLUT-4. Conclusion: 3T3-L1 cells, treated with LPV/RTV, show altered lipid content due to increased miRNA-218 levels, which affects lipin-1 mRNA. Moreover, increased miRNA-218 levels were inversely correlated with changes in GLUT-4 expression, which suggests a role for miRNA-218 in mediating the insulin resistance consequent to cART.

AB - Background: Metabolic complications represent a common and serious problem associated with HIV infection and combined Antiretroviral Therapy (cART). Alterations in body fat distribution are associated with significantly increased risks of (i) metabolic derangements, (ii) cardiovascular pathologies, and (iii) insulin resistance. A case control study showed that in subcutaneous adipose tissue from HIV-infected patients on cART presenting lipodystrophy (LS), the levels of miRNA-218 were upregulated and those of lipin-1, a putative target gene of miRNA-218, were downregulated compared with HIV-negative subjects. Lipin-1 is one of the most important factors linked to development of LS. Lipin-1, by controlling PPARγ2, regulates the expression of specific genes, such as that of glucose transporter type 4 (GLUT-4), required for maturation and maintenance of adipocytes. Objectives: To determine whether lopinavir/ritonavir (LPV/RTV) can modulate lipogenesis in adipocytes affecting miRNA-218 and lipin-1 mRNA expression, and to investigate the functional link between miRNA-218 and GLUT-4 mRNA expression. Methods: Differentiated 3T3-L1 cells were treated with various combinations of LPV/RTV, followed by measurements of cell viability, lipid accumulation, lipin-1 and GLUT-4 mRNA and miRNA-218 levels. Transfection of anti-miR-218 or a miRNA-218 mimic were used to investigate the role of miRNA-218 in lipogenesis. Results: LPV/RTV treatment of 3T3-L1 cells did not affect the viability of differentiated 3T3-L1 cells, but caused (i) a significant decrease of lipid accumulation, (ii) an overexpression of miRNA-218, and (iii) a reduction of lipin-1 and GLUT-4 mRNA levels. The anti-miR-218 transfection of 3T3-L1 cells significantly ameliorated the adipogenic dysfunction and restored mRNA levels of lipin-1 and GLUT-4 consequent to LPV/RTV treatment. By contrast, 3T3-L1 cells transfected with a specific miRNA-218 mimic showed (i) an overexpression of miRNA-218, (ii) a reduced cellular lipid fraction, and (iii) decreased levels of mRNA for lipin-1 and GLUT-4. Conclusion: 3T3-L1 cells, treated with LPV/RTV, show altered lipid content due to increased miRNA-218 levels, which affects lipin-1 mRNA. Moreover, increased miRNA-218 levels were inversely correlated with changes in GLUT-4 expression, which suggests a role for miRNA-218 in mediating the insulin resistance consequent to cART.

KW - Adipocyte

KW - HIV protease inhibitors

KW - Insulin resistance

KW - Lipodystrophy

KW - MiRNA

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