PT - JOURNAL ARTICLE AU - Huan Liu AU - Margaret Hallauer Hastings AU - Robert Kitchen AU - Chunyang Xiao AU - Justin Ralph Baldovino Guerra AU - Alexandra Kuznetsov AU - Anthony Rosenzweig TI - Beneficial Effects of Moderate Hepatic Activin A Expression on Metabolic pathways, Inflammation, and Atherosclerosis AID - 10.1101/2022.07.05.498830 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.07.05.498830 4099 - http://biorxiv.org/content/early/2022/07/05/2022.07.05.498830.short 4100 - http://biorxiv.org/content/early/2022/07/05/2022.07.05.498830.full AB - BACKGROUND Atherosclerosis is an inflammatory vascular disease marked by hyperlipidemia and hematopoietic stem cell (HSC) expansion. Activin A, a member of the Activin/GDF/TGFβ/BMP family is broadly expressed and increases in human atherosclerosis, but its functional effects in vivo in this context remain unclear.METHODS We studied LDLR-/- mice on a Western diet for 12 weeks and used adeno-associated viral vectors with a liver-specific thyroxine binding globulin (TBG) promoter to express Activin A or GFP (control). Atherosclerotic lesions were analyzed by oil red staining. Blood lipid profiling was performed by HPLC (High Performance Liquid Chromatography), and immune cells were evaluated by flow cytometry. Liver RNA-sequencing was performed to explore the underlying mechanisms.RESULTS Activin A expression decreased in both livers and aortae from LDLR-/- mice fed a Western diet compared with chow. AAV-TBG-Activin A increased Activin A hepatic expression (∼10-fold at 12-weeks, p<0.0001) and circulating Activin A levels (∼2000pg/ml vs ∼50pg/ml, p<0.001, compared with controls). Hepatic Activin A expression decreased plasma total and low-density lipoprotein (LDL) cholesterol (∼60% and ∼40%, respectively), reduced inflammatory cells in aortae and proliferating hematopoietic stem cells (HSC) in bone marrow, and reduced atherosclerotic lesion area in the aortic arch by ∼60%. Activin A also attenuated liver steatosis and expression of the lipogenesis genes, Srebp1 and Srebp2. RNA sequencing revealed Activin A not only blocked expression of genes involved in hepatic de novo lipogenesis but also fatty acid uptake, and liver inflammation. In addition, Activin A expressed in the liver also reduced white fat tissue accumulation, decreased adipocyte size, and improved glucose tolerance.CONCLUSIONS Our studies reveal hepatic Activin A expression reduces inflammation, HSC expansion, liver steatosis, circulating cholesterol, and fat accumulation, which likely all contribute to the observed protection against atherosclerosis. The reduced Activin A observed in LDLR-/- mice on a Western diet appears maladaptive and deleterious for atherogenesis.Competing Interest StatementThe authors have declared no competing interest.Non-standard Abbreviations and AcronymTBGthyroxine binding globulinCVDcardiovascular diseasesLDLlow density lipoproteinVLDLvery low-density lipoproteinoxLDL(oxidized-LDL)AAVadeno-associated virusFSTFollistatinHSChematopoietic stem cellLtHSClong-term hematopoietic stem cellStHSCshort-term hematopoietic stem cellMPPmultipotential progenitor cellsPMNpolymorphonuclear cellsDEGdifferentially expressed genesFAsfatty acids