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

• DOI: 10.7554/elife.92075.1
• Publication Date: 2023-12-01T13:23:46Z
• Authors: Christin Krause; Jan H. Britsemmer; Miriam Bernecker; Anna Molenaar; Natalie Taege; Cathleen Geißler; Meike Kaehler; Katharina Iben; Anna Judycka; Jonas Wagner; Stefan Wolter; Oliver Mann; Paul T. Pfluger; Ingolf Cascorbi; Hendrik Lehnert; Kerstin Stemmer; Sonja C. Schriever; Henriette Kirchner
• Keywords: Male; 0301 basic medicine; obesity; QH301-705.5; Science; liver; Mice; Animals; Humans; human; Obesity; Biology (General); 2. Zero hunger; ddc:610; 0303 health sciences; microRNA; Gene Expression Profiling; Q; R; Middle Aged; Fatty Liver; Mice, Inbred C57BL; MicroRNAs; Diabetes Mellitus, Type 2; Liver; Medicine; Female; type 2 diabetes; Transcriptome

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 map T2D induced changes the miRNAs landscape human liver samples, a subsequent robust identification validation target genes is still missing.Liver biopsies from age- gender-matched obese individuals with (n=20) or without were used for microRNA microarray analysis. candidate validated 85 subsequently mechanistically characterized cells well by dietary interventions overexpression mice.Here we present transcriptome use novel seed prediction tool robustly identify genes, which then unique cohort livers. Subsequent mouse studies identified distinct signature T2D-associated miRNAs, partly conserved both species. Of those, human-murine miR-182-5p was most associated whole-body glucose homeostasis lipid metabolism. Its gene LRP6 consistently lower expressed livers humans mice under conditions overexpression. Weight loss decreased restored Lrp6 expression other genes. Hepatic rapidly protein levels increased triglycerides fasting insulin obesogenic after only seven days.By mapping miRNA-transcriptome diabetic subjects, validating diet-induced mice, establishing miRNA tool, provide resource that will pave way future field. As proof concept, revealed repression miR-182-5p, promotes lipogenesis impairs homeostasis, provides mechanistic link between non-alcoholic fatty disease, demonstrate vivo can serve drug treatment obesity-driven steatosis.