
Upregulation of hepatic miR-182-5p in obese type 2 diabetic individuals represses the expression of the metabolic regulator LRP6, leading to impaired glucose homeostasis and increased hepatic lipogenesis.


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Background The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes is still missing.

Methods Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice.

Results Here we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5p was the most associated to whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5p overexpression. Weight loss in obese mice decreased hepatic miR-182-5p and restored Lrp6 expression and other miR-182-5p target genes. Hepatic overexpression of miR-182-5p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days.

Conclusion By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182-5p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis.

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### Competing Interest Statement

The authors have declared no competing interest.

*   ADA
    :   American Diabetes Association
    BMI
    :   body mass index
    DIO
    :   diet-induced obese
    miRNA
    :   microRNA
    HbA1c
    :   hemoglobin A1c
    NAFLD
    :   non-alcoholic fatty liver disease
    NAS
    :   NAFLD activity score
    ND
    :   non-diabetic
    qPCR
    :   quantitative real-time polymerase chain reaction
    STROBE
    :   STrengthening the Reporting of OBservational studies in Epidemiology
    T2D
    :   type 2 diabetes
    UTR
    :   untranslated region

 [1]: pending:yes

Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity

hepatic-microrna-mir-182-5p-links-type-2-diabetes-and-fatty-liver-disease-in-obesity


Hepatic microRNA miR-182-5p Links Type 2 Diabetes and Fatty Liver Disease in Obesity
