Hepatic transcript signatures predict atherosclerotic lesion burden prior to a 2-year high cholesterol, high fat diet challenge

Abstract

The purpose of this study was to identify molecular mechanisms by which the liver influences total lesion burden in a nonhuman primate model (NHP) of cardiovascular disease with acute and chronic feeding of a high cholesterol, high fat (HCHF) diet. Baboons (47 females, 64 males) were fed a HCHF diet for 2 years (y); liver biopsies were collected at baseline, 7 weeks (w) and 2y, and lesions were quantified in aortic arch, descending aorta, and common iliac at 2y. Unbiased weighted gene co-expression network analysis (WGCNA) revealed several modules of hepatic genes correlated with lesions at different time points of dietary challenge. Pathway and network analyses were performed to study the roles of hepatic module genes. More significant pathways were observed in males than females. In males, we found modules enriched for genes in oxidative phosphorylation at baseline, opioid signaling at 7w, and EIF2 signaling and HNF1A and HNF4A networks at baseline and 2y. One module enriched for fatty acid β oxidation pathway genes was found in males and females at 2y. To our knowledge, this is the first study of a large NHP cohort to identify hepatic genes that correlate with lesion burden. Correlations of baseline and 7w module genes with lesions at 2y were observed in males but not in females. Pathway analyses of baseline and 7w module genes indicate EIF2 signaling, oxidative phosphorylation, and μ-opioid signaling are possible mechanisms that predict lesion formation induced by HCHF diet consumption in males. Our findings of coordinated hepatic transcriptional response in male baboons but not female baboons indicate underlying molecular mechanisms differ between female and male primate atherosclerosis.

Disturbed flow impairs MerTK-mediated efferocytosis in aortic endothelial cells during atherosclerosis

“…It is note that the results of EIF2 downregulation is acquired by IPA with canonical pathways. Studies have shown that downregulation of EIF2 signaling promotes progression of atherosclerosis 33 that is consistent with our findings. As expected, the machine learning disease pathways show that MerTK gene deficiency is associated with occlusion artery disease, heart dysfunction and brain disorders.…”

Multi-omics Analysis of Aging Liver Reveals Changes in Endoplasmic Stress and Degradation Pathways in Female Nonhuman Primates

“…NHPs are ideal translational models because they share strikingly similar genetic, physiological, and behavior traits with humans (Tarantal et al 2022). Our recent NHP studies aim to better understand human disease processes have focused on genetics, epigenetics, caloric restriction, maternal caloric restriction and offspring health, maternal obesity and offspring health, NASH, and steatosis (Zimmerman et al 2023, Puppala et al 2022. In humans, studies comparing diseased vs. healthy liver have shown decline in cellular and biological functions (Wang et al 2023, Campagnoli et al 2022.…”