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.