Hepatic Forkhead Box Protein A3 Regulates ApoA-I (Apolipoprotein A-I) Expression, Cholesterol Efflux, and Atherogenesis
activation; Atherosclerosis; Cardiovascular System & Cardiology; cholesterol efflux; fatty-acids; FOXA3; FOXA3; gene; Hematology; high-density-lipoprotein; increased; Liver; Macrophages; mice lacking; nuclear factor 3-gamma; transport
OBJECTIVE: To determine the role of hepatic FOXA3 (forkhead box A3) in lipid metabolism and atherosclerosis. Approach and Results: Hepatic FOXA3 expression was reduced in diabetic or high fat diet-fed mice or patients with nonalcoholic steatohepatitis. We then used adenoviruses to overexpress or knock down hepatic FOXA3 expression. Overexpression of FOXA3 in the liver increased hepatic ApoA-I (apolipoprotein A-I) expression, plasma HDL-C (high-density lipoprotein cholesterol) level, macrophage cholesterol efflux, and macrophage reverse cholesterol transport. In contrast, knockdown of hepatic FOXA3 expression had opposite effects. We further showed that FOXA3 directly bound to the promoter of the Apoa1 gene to regulate its transcription. Finally, AAV8 (adeno-associated virus serotype 8)-mediated overexpression of human FOXA3 in the hepatocytes of Apoe-/- (apolipoprotein E-deficient) mice raised plasma HDL-C levels and significantly reduced atherosclerotic lesions. CONCLUSIONS: Hepatocyte FOXA3 protects against atherosclerosis by inducing ApoA-I and macrophage reverse cholesterol transport.
Li Yuanyuan; Xu Yanyong; Jadhav Kavita; Zhu Yingdong; Yin Liya; Zhang Yanqiao
Arteriosclerosis, Thrombosis, and Vascular Biology
2019
2019-08
<a href="http://doi.org/10.1161/ATVBAHA.119.312610" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.119.312610</a>
TSP-1 (thrombospondin-1) deficiency protects APOE(-/-) mice against leptin-induced atherosclerosis.
atherosclerosis; leptin; obesity; smooth muscle; thrombospondins
OBJECTIVE: Hyperleptinemia, hallmark of obesity, is a putative pathophysiologic trigger for atherosclerosis. We previously reported a stimulatory effect of leptin on TSP-1 (thrombospondin-1) expression, a proatherogenic matricellular protein implicated in atherogenesis. However, a causal role of TSP-1 in leptin-driven atherosclerosis remains unknown. Approach and Results: Seventeen-weeks-old ApoE(-/-) and TSP-1(-/-)/ApoE(-/-) double knockout mice, on normocholesterolemic diet, were treated with or without murine recombinant leptin (5 µg/g bwt, IP) once daily for 3 weeks. Using aortic root morphometry and en face lesion assay, we found that TSP-1 deletion abrogated leptin-stimulated lipid-filled lesion burden, plaque area, and collagen accumulation in aortic roots of ApoE(-/-) mice, shown via Oil red O, hematoxylin and eosin, and Masson trichrome staining, respectively. Immunofluorescence microscopy of aortic roots showed that TSP-1 deficiency blocked leptin-induced inflammatory and smooth muscle cell abundance as well as cellular proliferation in ApoE(-/-) mice. Moreover, these effects were concomitant to changes in VLDL (very low-density lipoprotein)-triglyceride and HDL (high-density lipoprotein)-cholesterol levels. Immunoblotting further revealed reduced vimentin and pCREB accompanied with augmented smooth muscle-myosin heavy chain expression in aortic vessels of leptin-treated double knockout versus leptin-treated ApoE(-/-); also confirmed in aortic smooth muscle cells from the mice genotypes, incubated ± leptin in vitro. Finally, TSP-1 deletion impeded plaque burden in leptin-treated ApoE(-/-) on western diet, independent of plasma lipid alterations. CONCLUSIONS: The present study provides evidence for a protective effect of TSP-1 deletion on leptin-stimulated atherogenesis. Our findings suggest a regulatory role of TSP-1 on leptin-induced vascular smooth muscle cell phenotypic transition and inflammatory lesion invasion. Collectively, these results underscore TSP-1 as a potential target of leptin-induced vasculopathy.
Ganguly R; Khanal S; Mathias A; Gupta S; Lallo J; Sahu S; Ohanyan VA; Patel A; Storm K; Datta S; Raman P
Arteriosclerosis, Thrombosis, and Vascular Biology
2020
2020-12-17
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1161/ATVBAHA.120.314962" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.120.314962</a>
Step by Step: Advancing the Understanding of Local Vascular Control.
Editorials; vasodilation; hypoxia; dilation; endothelium; arterial pressure
Chilian William M; Yin Liya; Ohanyan Vahagn
Arteriosclerosis, thrombosis, and vascular biology
2020
2020-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1161/ATVBAHA.120.313811" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.120.313811</a>