Diet and gut microbiota orchestrate the hepatic endothelial transcriptome in atherosclerosis

Introduction The gut-liver axis is a bidirectional system, which markedly influences remote metabolic functions of the host and is involved in the development of atherosclerosis. By delivering microbial components through the portal vein, the gut microbiota was shown to modulate the cholesterol and lipid metabolism in the hepatic endothelium. Yet, how diet, a significant modifier of gut microbial communities, affects the hepatic endothelium remains limitedly understood. In this study, we shed light on the diet-dependent effects on the transcriptome of liver endothelial cells (LECs) during the progression of both early and late-stage atherosclerosis.

Method Low-density lipoprotein receptor-deficient mice (Ldlr ^-/-) were housed in either germ-free (GF) or conventionally raised (CONV-R) conditions and fed with high-fat Western diet (HFD) or standard chow diet (ND) for 16 weeks. Following isolation of LECs using a magnetic cell separation technique, whole-transcriptome sequencing analysis was performed. To dissect the influence of microbiome and diet at early time points, the effect of 8 weeks of feeding with ND or HFD on the LEC transcriptome, mRNA and protein expression was investigated. Furthermore, the aortic root and aortic arch lesion size was histologically quantified.

Results In CONV-R Ldlr ^-/- mice, fed with HFD for 16 weeks, cholesterol homeostasis and inflammatory responses in the hepatic endothelial transcriptome were deregulated. Interestingly, no significant regulation in the sphingolipid metabolism was identified. However, in early atherosclerosis Ldlr ^-/- mice exhibited diet-dependent regulations of the key enzymes sphingomyelin synthase-1 (Sms1) and sphingomyelin phosphodiesterase 3 (Smpd3) in LECs, suggesting dynamic changes of endothelial lipid synthesis pathways in the progression of atherosclerosis. Since sphingolipids were shown to be involved in atherogenesis, atherosclerotic plaques in aortic roots and aortic arch of GF and CONV-R Ldlr ^-/- mice were histologically analyzed. However, atherosclerotic lesion size in early atherosclerosis was unchanged at the studied conditions.

Conclusion Here, we report that the gut microbiota and diet dynamically modify the expression profile of enzymes involved in cholesterol and sphingolipid metabolism in the hepatic endothelium in a mouse model of early atherosclerosis.

Publication History

Article published online:
26 February 2024