Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), 2333 CK Leiden, The Netherlands.
Department of Microbiology and Systems Biology, The Netherlands Organization for Applied Scientific Research (TNO), 3704 HE Zeist, The Netherlands.
Int J Mol Sci. 2022 Jul 26;23(15):8229. doi: 10.3390/ijms23158229.
The prevalence of non-alcoholic steatohepatitis (NASH) is rapidly increasing and associated with cardiovascular disease (CVD), the major cause of mortality in NASH patients. Although sharing common risk factors, the mechanisms by which NASH may directly contribute to the development to CVD remain poorly understood. The aim of this study is to gain insight into key molecular processes of NASH that drive atherosclerosis development. Thereto, a time-course study was performed in Ldlr-/-.Leiden mice fed a high-fat diet to induce NASH and atherosclerosis. The effects on NASH and atherosclerosis were assessed and transcriptome analysis was performed. Ldlr-/-.Leiden mice developed obesity, hyperlipidemia and insulin resistance, with steatosis and hepatic inflammation preceding atherosclerosis development. Transcriptome analysis revealed a time-dependent increase in pathways related to NASH and fibrosis followed by an increase in pro-atherogenic processes in the aorta. Gene regulatory network analysis identified specific liver regulators related to lipid metabolism (SC5D, LCAT and HMGCR), inflammation (IL1A) and fibrosis (PDGF, COL3A1), linked to a set of aorta target genes related to vascular inflammation (TNFA) and atherosclerosis signaling (CCL2 and FDFT1). The present study reveals pathogenic liver processes that precede atherosclerosis development and identifies hepatic key regulators driving the atherogenic pathways and regulators in the aorta.
非酒精性脂肪性肝炎（NASH）的患病率正在迅速上升，与心血管疾病（CVD）相关，是 NASH 患者死亡的主要原因。尽管具有共同的危险因素，但 NASH 如何直接导致 CVD 的发病机制仍知之甚少。本研究旨在深入了解导致动脉粥样硬化发展的 NASH 的关键分子过程。为此，在 Ldlr-/-.Leiden 小鼠中进行了一项时间进程研究，这些小鼠喂食高脂肪饮食以诱导 NASH 和动脉粥样硬化。评估了对 NASH 和动脉粥样硬化的影响，并进行了转录组分析。Ldlr-/-.Leiden 小鼠发生肥胖、高血脂和胰岛素抵抗，脂肪变性和肝炎症先于动脉粥样硬化的发展。转录组分析显示，与 NASH 和纤维化相关的途径随着时间的推移呈上升趋势，随后主动脉中出现促动脉粥样硬化过程增加。基因调控网络分析确定了与脂质代谢（SC5D、LCAT 和 HMGCR）、炎症（IL1A）和纤维化（PDGF、COL3A1）相关的特定肝脏调节剂，与一组与血管炎症（TNFA）和动脉粥样硬化信号（CCL2 和 FDFT1）相关的主动脉靶基因相关。本研究揭示了先于动脉粥样硬化发展的致病肝脏过程，并确定了肝脏中驱动主动脉中动脉粥样硬化途径和调节剂的关键调节剂。
