Human Insulin Growth Factor 2 mRNA Binding Protein 2 Increases MicroRNA 33a/b Inhibition of Liver ABCA1 Expression and Alters Low-Density Apolipoprotein Levels in Mice

ABSTRACT

Genome-wide association studies (GWAS) have linked IGF2BP2 single-nucleotide polymorphisms (SNPs) with type 2 diabetes (T2D). Mice overexpressing mIGF2BP2 have elevated cholesterol levels when fed a diet that induces hepatic steatosis. These and other studies suggest an important role for insulin growth factor 2 mRNA binding protein 2 (IGF2BP2) in the initiation and progression of several metabolic disorders. The ATPase binding cassette protein ABCA1 initiates nascent high-density apolipoprotein (HDL) biogenesis by transferring phospholipid and cholesterol to delipidated apolipoprotein AI (ApoAI). Individuals with mutational ablation of ABCA1 have Tangier disease, which is characterized by a complete loss of HDL. MicroRNA 33a and 33b (miR-33a/b) bind to the 3′ untranslated region (UTR) of ABCA1 and repress its posttranscriptional gene expression. Here, we show that IGF2BP2 works together with miR-33a/b in repressing ABCA1 expression. Our data suggest that IGF2BP2 is an accessory protein of the argonaute (AGO2)–miR-33a/b–RISC complex, as it directly binds to miR-33a/b, AGO2, and the 3′ UTR of ABCA1. Finally, we show that mice overexpressing human IGF2BP2 have decreased ABCA1 expression, increased low-density lipoprotein-cholesterol (LDL-C) and cholesterol blood levels, and elevated SREBP-dependent signaling. Our data support the hypothesis that IGF2BP2 has an important role in maintaining lipid homeostasis through its modulation of ABCA1 expression, as its overexpression or loss leads to dyslipidemia.

KEYWORDS:

• lipid
• fatty acids
• ABCA1
• IGF2BP2
• LDL-C
• SREBP
• cholesterol
• triglyceride
• high-density lipoprotein
• HDL
• very low-density lipoprotein
• VLDL
• DICER
• LDL
• lipid
• microRNA
• reverse cholesterol transport

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SUPPLEMENTAL MATERIAL

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ACKNOWLEDGMENTS

We appreciate the discussions with members of the Institute of Metabolic Disorders, Invivotek, and Genesis Biotechnology Group. We are grateful to the members of Invivotek for performing the mouse studies.

We acknowledge the financial support of Genesis Biotechnology Group. V.M. was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R15GM132853.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

We declare no conflicts of interest.

J.T.N. and M.Y. cowrote the manuscript. J.T.N., M.Y., V.M., M.H., and C.G.-E. designed the experiments and interpreted the data. M.Y., W.L., V.M., and C.G.-E. performed the experiments.