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

• Published in: eLife 2024-07, Vol.12
• Main Authors: Krause, Christin, Britsemmer, Jan H, Bernecker, Miriam, Molenaar, Anna, Taege, Natalie, Lopez-Alcantara, Nuria, Geißler, Cathleen, Kaehler, Meike, Iben, Katharina, Judycka, Anna, Wagner, Jonas, Wolter, Stefan, Mann, Oliver, Pfluger, Paul, Cascorbi, Ingolf, Lehnert, Hendrik, Stemmer, Kerstin, Schriever, Sonja C, Kirchner, Henriette
• Format: Article
• Language: English
• Subjects: Animals; Antidiabetics; Biopsy; Body fat; Body weight loss; Comorbidity; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diet; DNA microarrays; Epigenetics; Fatty liver; Fatty Liver - genetics; Fatty Liver - metabolism; Female; Gastrointestinal surgery; Gene expression; Gene Expression Profiling; Gene mapping; Glucose; Glucose metabolism; Hepatocytes; Homeostasis; human; Humans; Insulin resistance; Lipid metabolism; Lipogenesis; Liver; Liver - metabolism; Liver diseases; LRP6 protein; Male; Medicine; Metabolism; Mice; Mice, Inbred C57BL; microRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miRNA; Obesity; Obesity - genetics; Obesity - metabolism; Peptide mapping; Signal transduction; Steatosis; Therapeutic targets; Transcriptome; Transcriptomes; Triglycerides; type 2 diabetes
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.92075

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 are still missing. 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. 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-182-5 p was the most associated with whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5 p overexpression. Weight loss in obese mice decreased hepatic miR-182-5 p and restored expression and other miR-182-5 p target genes. Hepatic overexpression of miR-182-5 p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days. 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 by miR-182-5 p, 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-182-5 p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis. This work was supported by research funding from the Deutsche Forschungsgemeinschaft (KI 1887/2-1, KI 1887/2-2, KI 1887/3-1 and CRC-TR296), the European Research Council (ERC, CoG Yoyo LepReSens no. 101002247; PTP), t