Trans-chalcone enhances insulin sensitivity through the miR-34a/SIRT1 pathway

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Abstract

Objective(s):

Trans-chalcone as the parent member of the chalcone series reduces circulating levels of insulin and glucose. However, the cellular mechanism of these effects is poorly understood. Sirtuin 1 (SIRT1) as a direct target of miR-34a controls homeostasis of glucose, and also improves insulin sensitivity. Therefore, the present study for the first time investigated the influence of trans-chalcone on the miR-34a/SIRT1 pathway as a possible mechanism for its hypoglycemic and hypoinsulinemic effects.

Materials and Methods:

In this study, thirty male rats were randomly divided into three groups (n=10): solvent control (NS), oral administration of trans-chalcone for 2 (N2T) and 6 weeks (N6T) groups. Then, hepatic levels of miR-34a and SIRT1 were measured through the qRT-PCR method.

Results:

Trans-chalcone reduced food intake, body weight gain, and serum glucose as well as insulin levels. Also, this chalcone inhibited hepatic miR-34a expression and significantly elevated SIRT1 mRNA level.

Conclusion:

Trans-chalcone as an insulin-sensitizing chalcone partly acts through the miR-34a/SIRT1 pathway.

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Most cited references 29

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miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease.

Rui E. Castro, Duarte M.S. Ferreira, Marta Afonso … (2013)

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of stages from simple steatosis to non-alcoholic steatohepatitis (NASH). However, disease pathogenesis remains largely unknown. microRNA (miRNA or miR) expression has recently been reported to be altered in human NASH, and modulated by ursodeoxycholic acid (UDCA) in the rat liver. Here, we aimed at evaluating the miR-34a/Sirtuin 1(SIRT1)/p53 pro-apoptotic pathway in human NAFLD, and to elucidate its function and modulation by UDCA in the rat liver and primary rat hepatocytes. Liver biopsies were obtained from NAFLD morbid obese patients undergoing bariatric surgery. Rat livers were collected from animals fed a 0.4% UDCA diets. Primary rat hepatocytes were incubated with bile acids or free fatty acids (FFAs) and transfected with a specific miRNA-34a precursor and/or with a p53 overexpression plasmid. p53 transcriptional activity was assessed by ELISA and target reporter constructs. miR-34a, apoptosis and acetylated p53 increased with disease severity, while SIRT1 diminished in the NAFLD liver. UDCA inhibited the miR-34a/SIRT1/p53 pathway in the rat liver in vivo and in primary rat hepatocytes. miR-34a overexpression confirmed its targeting by UDCA, which prevented miR-34a-dependent repression of SIRT1, p53 acetylation, and apoptosis. Augmented apoptosis by FFAs in miR-34a overexpressing cells was also inhibited by UDCA. Finally, p53 overexpression activated miR-34a/SIRT1/p53, which in turn was inhibited by UDCA, via decreased p53 transcriptional activity. Our results support a link between liver cell apoptosis and miR-34a/SIRT1/p53 signaling, specifically modulated by UDCA, and NAFLD severity. Potential endogenous modulators of NAFLD pathogenesis may ultimately provide new tools for therapeutic intervention. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT.

Sung-E Choi, Xiao-ting Fu, Sunmi Seok … (2013)

SIRT1 is an NAD(+)-dependent deacetylase that is implicated in prevention of many age-related diseases including metabolic disorders. As SIRT1 deacetylase activity is dependent on NAD(+) levels and the development of compounds that directly activate SIRT1 has been controversial, indirectly activating SIRT1 through enhancing NAD(+) bioavailability has received increasing attention. NAD(+) levels are reduced in obesity and the aged, but the underlying mechanisms remain unclear. We recently showed that hepatic microRNA-34a (miR-34a), which is elevated in obesity, directly targets and decreases SIRT1 expression. Here, we further show that miR-34a reduces NAD(+) levels and SIRT1 activity by targeting NAMPT, the rate-limiting enzyme for NAD(+) biosynthesis. A functional binding site for miR-34a is present in the 3' UTR of NAMPT mRNA. Hepatic overexpression of miR-34a reduced NAMPT/NAD(+) levels, increased acetylation of the SIRT1 target transcriptional regulators, PGC-1α, SREBP-1c, FXR, and NF-κB, and resulted in obesity-mimetic outcomes. The decreased NAMPT/NAD(+) levels were independent of miR-34a effects on SIRT1 levels as they were also observed in SIRT1 liver-specific knockout mice. Further, the miR-34a-mediated decreases were reversed by treatment with the NAD(+) intermediate, nicotinamide mononucleotide. Conversely, antagonism of miR-34a in diet-induced obese mice restored NAMPT/NAD(+) levels and alleviated steatosis, inflammation, and glucose intolerance. Anti-miR-34a-mediated increases in NAD(+) levels were attenuated when NAMPT was downregulated. Our findings reveal a novel function of miR-34a in reducing both SIRT1 expression and activity in obesity. The miR-34a/NAMPT axis presents a potential target for treating obesity- and aging-related diseases involving SIRT1 dysfunction like steatosis and type 2 diabetes.

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Influence of miRNA in insulin signaling pathway and insulin resistance: micro-molecules with a major role in type-2 diabetes.

Chiranjib Chakraborty, C Doss, Sanghamitra Bandyopadhyay … (2024)

The prevalence of type-2 diabetes (T2D) is increasing significantly throughout the globe since the last decade. This heterogeneous and multifactorial disease, also known as insulin resistance, is caused by the disruption of the insulin signaling pathway. In this review, we discuss the existence of various miRNAs involved in regulating the main protein cascades in the insulin signaling pathway that affect insulin resistance. The influence of miRNAs (miR-7, miR-124a, miR-9, miR-96, miR-15a/b, miR-34a, miR-195, miR-376, miR-103, miR-107, and miR-146) in insulin secretion and beta (β) cell development has been well discussed. Here, we highlight the role of miRNAs in different significant protein cascades within the insulin signaling pathway such as miR-320, miR-383, miR-181b with IGF-1, and its receptor (IGF1R); miR-128a, miR-96, miR-126 with insulin receptor substrate (IRS) proteins; miR-29, miR-384-5p, miR-1 with phosphatidylinositol 3-kinase (PI3K); miR-143, miR-145, miR-29, miR-383, miR-33a/b miR-21 with AKT/protein kinase B (PKB) and miR-133a/b, miR-223, miR-143 with glucose transporter 4 (GLUT4). Insulin resistance, obesity, and hyperlipidemia (high lipid levels in the blood) have a strong connection with T2D and several miRNAs influence these clinical outcomes such as miR-143, miR-103, and miR-107, miR-29a, and miR-27b. We also corroborate from previous evidence how these interactions are related to insulin resistance and T2D. The insights highlighted in this review will provide a better understanding on the impact of miRNA in the insulin signaling pathway and insulin resistance-associated diagnostics and therapeutics for T2D.

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Author and article information

Journal

Journal ID (nlm-ta): Iran J Basic Med Sci

Journal ID (iso-abbrev): Iran J Basic Med Sci

Title: Iranian Journal of Basic Medical Sciences

Publisher: Mashhad University of Medical Sciences (Iran )

ISSN (Print): 2008-3866

ISSN (Electronic): 2008-3874

Publication date (Print): April 2018

Volume: 21

Issue: 4

Pages: 359-363

Affiliations

[1 ]Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

[2 ]Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

[3 ]Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Author notes

[* ] Corresponding author: Mohammad Reza Alipour. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Tel/Fax: +98-4133364664; Email: alipourmr52@ 123456gmail.com ; alipourmr52@ 123456gmail.com

Article

Publisher ID: IJBMS-21-359

DOI: 10.22038/IJBMS.2018.24300.6063

PMC ID: 5960750

PubMed ID: 29796217

SO-VID: 88034f96-d292-455f-b683-ab3257f284ae

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Trans-chalcone enhances insulin sensitivity through the miR-34a/SIRT1 pathway

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Abstract

Objective(s):

Materials and Methods:

Results:

Conclusion:

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Microbiology Independent Research Journal (MIR Journal)

Most cited references 29

miR-34a/SIRT1/p53 is suppressed by ursodeoxycholic acid in the rat liver and activated by disease severity in human non-alcoholic fatty liver disease.

Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT.

Influence of miRNA in insulin signaling pathway and insulin resistance: micro-molecules with a major role in type-2 diabetes.

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