Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance

Abstract

SUMMARYWhile therapeutic modulation of miRNAs provides a promising approach for numerous diseases, the promiscuous nature of miRNAs raises concern over detrimental off-target effects. miR-33 has emerged as a likely target for treatment of cardiovascular diseases. However, the deleterious effects of long-term anti-miR-33 therapies and predisposition of miR-33−/− mice to obesity and metabolic dysfunction exemplify the possible pitfalls of miRNA-based therapies. Our work provides an in-depth characterization of miR-33−/− mice and explores the mechanisms by which loss of miR-33 promotes insulin resistance in key metabolic tissues. Contrary to previous reports, our data do not support a direct role for SREBP-1-mediated lipid synthesis in promoting these effects. Alternatively, in adipose tissue of miR-33−/− mice, we observe increased pre-adipocyte proliferation, enhanced lipid uptake, and impaired lipolysis. Moreover, we demonstrate that the driving force behind these abnormalities is increased food intake, which can be prevented by pair feeding with wild-type animals.

Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation

“…Therefore, miR-33a and SREBP2 act synergistically to efficiently increase cellular cholesterol levels by inhibiting cellular cholesterol efflux and increasing lipid uptake and intracellular synthesis, respectively. While previous studies suggested that miR-33 may represent therapeutic target for the treatment of cardiovascular disease [24,25], a recent work showed that miR-33 deletion in mice results in dyslipidemia, obesity, and insulin resistance [26], assigning a role for miR-33 that is much more complex than what has been considered so far. Such complexity has also been illustrated in humans by the fact that miR-33 levels are surprisingly elevated in pediatric patients affected by familial hypercholesterolemia (FH) [27].…”

A Novel Regulatory Circuit “C/EBPα/miR-20a-5p/TOB2” Regulates Adipogenesis and Lipogenesis

“…Moreover, some microRNAs have been implicated in dietinduced obesity. Data from Price et al showed that miR-33 null mice had increased food intake, enhanced adipose tissue expansion, and a predisposition to develop diet-induced obesity and insulin resistance (17). miR-143 was found to be upregulated in mesenteric fat of high-fat diet-induced mice (18).…”

Targeted suppression of microRNA-33 in lesional macrophages using pH low-insertion peptides (pHLIP) improves atherosclerotic plaque regression

“…Our group and others initially identi ed microRNA-33 (miR-33) as crucial regulator of cellular lipid homeostasis and lipoprotein metabolism, controlling downstream target genes including ABCA1 and ABCG1 10,11,12,13,14,15,16 . The bene ts of miR-33 de ciency on atherosclerosis development are attributed to its protective effects in macrophages 12 Therapeutic inhibition of miR-33 in the mice and non-human primates raises plasma high density lipoprotein (HDL) levels and inhibits the progression of atherosclerosis by increasing HDL levels/functionality or enhancing cholesterol e ux through induction of ABCA1 and ABCG1 in macrophages 14,15,16,17 .…”