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Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, glucose production and its absence alters liver disease progression (F480+ CELLS)

ABSTRACT: Elevated circulating dipeptidyl-peptidase 4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and metabolic associated fatty liver disease (MAFLD) progression remains unclear. Here we identified that DPP4 in hepatocytes but not Tie2+ endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of Dpp4-/- mice displayed enrichment for inflammasome, p53, and senescence programs compared to littermate controls. High-fat high-cholesterol (HFHC)-feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE218766 | GEO | 2023/01/31

REPOSITORIES: GEO

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Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, glucose production and its absence alters liver disease progression (LIVER)

Project description:Elevated circulating dipeptidyl-peptidase 4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and metabolic associated fatty liver disease (MAFLD) progression remains unclear. Here we identified that DPP4 in hepatocytes but not Tie2+ endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of Dpp4-/- mice displayed enrichment for inflammasome, p53, and senescence programs compared to littermate controls. High-fat high-cholesterol (HFHC)-feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling.

2023-01-31 | GSE218765 | GEO

LncRNA expression profile and target gene prediction of calcification in human aortic smooth muscle cells induced by DPP4

Project description:Arterial media calcification caused by diabetes is an important cause of vascular calcification. Dipeptidyl peptidase-4 (DPP4) is associated with diabetic arterial media calcification. At the same time, long non-coding RNA(lncRNA) is closely related to the evolution of a variety of cardiovascular diseases, but the involvement of lncRNA in vascular calcification induced by DPP4 has not been reported in details. In this study, we established a model of human aortic smooth muscle cells (HASMCs) calcification induced by DPP4. There was a significant difference in the expression of lncRNAs and mRNAs between normal and calcified vascular smooth muscle cells detected by gene chip technology. Based on the results of microarray detection, we found that lncRNA may be involved in vascular calcification induced by DPP4 through regulating target genes.

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Chemically induced expansion of type 2 alveolar epithelial cell promotes regenerative lower airway repair [RNA-seq]

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Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, glucose production and its absence alters liver disease progression

Project description:This SuperSeries is composed of the SubSeries listed below.

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Senohemostatic role for DPP4 in atherosclerosis

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Repurposing DPP4-Inhibition to Improve Hair Follicle Activation and Regeneration

Project description:Skin-injury and several diseases elicit fibrosis and induce hair follicle (HF)-growth arrest and loss. Resulting alopecia and disfiguration represent a severe burden for patients both physically and psychologically. Reduction of pro-fibrotic factors such as DPP4 might be a strategy to tackle this issue. We demonstrate DPP4-overrepresentation in settings with HF-growth arrest (telogen), HF-loss and non-regenerative wound areas in mice skin and human scalp. Topical DPP4-inhibition (DPP4i) with FDA/EMA-approved Sitagliptin (Sit) on preclinical models of murine HF-activation/regeneration results in accelerated anagen-progress, while treatment of wounds with Sit results in reduced expression of fibrosis markers, increased induction of anagen around wounds, and HF-regeneration in the wound center. These effects are associated with higher expression of Wnt-target Lef1, known to be required for HF-anagen (HF-activation)/regeneration. Sit-treatment decreases pro-fibrotic signaling in the skin, induce a differentiation trajectory of HF-cells, and activate Wnt-targets related to HF-activation/growth but not those supporting fibrosis. Taken together, our study demonstrates a role for DPP4 in HF biology and shows how DPP4i, currently used as oral medication to treat diabetes, could be repurposed into a topical treatment agent to potentially reverse HF-loss in alopecia and after injury.

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Project description:Dipeptidyl peptidase-4 (Dpp4) inhibitors are used worldwide to combat diabetes, however, their roles in cardiovascular disorders are yet to be defined. Here we show that a DPP4 inhibitor, linagliptin, contributes for the suppression of capillary rarefaction in cardiac tissues of dietary obese mice model. Imposing a high fat diet into mice induced capillary rarefaction and cardiac dysfunction. These pathologies associated with high DPP4 level in circulation, and the administration of linagliptin into dietary obese mice suppressed the development of capillary rarefaction and ameliorated cardiac dysfunction. Early growth response protein 1 (EGR1), known as an angiogenic transcription factor, is significantly reduced in the cardiac tissue upon metabolic stress, and this suppression was inhibited by the administration of linagliptin.

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