Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Feb;66(2):347-357.
doi: 10.2337/db16-0731. Epub 2016 Nov 29.

Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes

Peter Willeit  1   2   3 , Philipp Skroblin  4 , Alexander R Moschen  5 , Xiaoke Yin  4 , Dorothee Kaudewitz  4 , Anna Zampetaki  4 , Temo Barwari  4 , Meredith Whitehead  4 , Cristina M Ramírez  6 , Leigh Goedeke  6 , Noemi Rotllan  6 , Enzo Bonora  7 , Alun D Hughes  8 , Peter Santer  9 , Carlos Fernández-Hernando  6 , Herbert Tilg  5 , Johann Willeit  2 , Stefan Kiechl  2 , Manuel Mayr  1
Affiliations

Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes

Peter Willeit et al. Diabetes. 2017 Feb.

Abstract

MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent insulin resistance, obesity, metabolic syndrome, type 2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122-treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30-1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03-1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population.

PubMed Disclaimer

Conflict of interest statement

Duality of Interest. The Medical University of Innsbruck and King’s College London filed patent applications on miRNA biomarkers.

Figures

Figure 1
Figure 1
Cross-sectional correlation of serum miR-122 levels with lipid subspecies (A) and selected proteins related to lipid metabolism (B) in the Bruneck Study. In A, lipid species are arranged by lipid class in eight panels according to the number of total carbon atoms and number of double bonds. Lipid species highlighted with a yellow halo showed statistically significant correlations after Bonferroni correction. For better visibility, those lipid species with alkyl ether linkage are shifted upwards, whereas their alkyl ether–free counterparts are shifted downward. In B, P values significant after Bonferroni correction are shown in bold. The full panel of proteins is shown in Supplementary Fig. 2. AFAM, afamin; CE, cholesteryl ester; CFAH, complement factor H; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; SM, sphingomyelin; TAG, triacylglycerol; ZA2G, zinc-α-2-glycoprotein.
Figure 2
Figure 2
Effects of antagomiR-122 injection in mice. Panels show liver miR-122 expression assessed by Northern blotting (A), expression of other hepatic miRNAs involved in lipoprotein metabolism (B), serum cholesterol (C), gene expression (D), and hepatic proteome profile (E). Two proteomics methods were used for quantitation: a label-free method based on spectral counting and a 10-plex experiment using TMT labeling. Proteins that were returned as differentially expressed by both techniques are highlighted (for details see Supplementary Tables 1 and 2). Acc1, acetyl-CoA carboxylase; Aldo, aldolase; CP2AC, cytochrome P450 2A12; Fasn, fatty acid synthase; GRN, granulins; Hmgcr, HMG-CoA reductase; Ldlr, LDL receptor; RL23A, 60S ribosomal protein L23a; RL37A, 60S ribosomal protein L37a; RS16, 40S ribosomal protein S16; RS18, 40S ribosomal protein S18; Scd1, stearoyl-CoA desaturase-1.
Figure 3
Figure 3
Effects of atorvastatin treatment on total cholesterol (Total-C), LDL cholesterol (LDL-C) (A), and serum miR-122 in ASCOT participants (B), serum miR-122 in mice (C), and miR-122 secretion from primary hepatocytes (D).
Figure 4
Figure 4
Association of miR-122 with new-onset metabolic syndrome and T2D in the Bruneck Study. Multivariable model (*): age, sex, socioeconomic status, smoking, physical activity, and alcohol consumption. WHR, waist-to-hip ratio.
Figure 5
Figure 5
Summary of the key findings. AFAM, afamin; CM, chylomicrons; TG, triglycerides; ZA2G, zinc-α-2-glycoprotein.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215–233 - PMC - PubMed
    1. Fernández-Hernando C, Ramírez CM, Goedeke L, Suárez Y. MicroRNAs in metabolic disease. Arterioscler Thromb Vasc Biol 2013;33:178–185 - PMC - PubMed
    1. Willeit P, Skroblin P, Kiechl S, Fernández-Hernando C, Mayr M. Liver microRNAs: potential mediators and biomarkers for metabolic and cardiovascular disease? Eur Heart J 2016;37:3260–3266 - PMC - PubMed
    1. Esau C, Davis S, Murray SF, et al. . miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006;3:87–98 - PubMed
    1. Krützfeldt J, Rajewsky N, Braich R, et al. . Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005;438:685–689 - PubMed

MeSH terms