Loss of embryonically-derived Kupffer cells during hypercholesterolemia accelerates atherosclerosis development

Abstract

AbstractHypercholesterolemia is a major risk factor for atherosclerosis and associated cardiovascular diseases. The liver plays a key role in the regulation of plasma cholesterol levels and hosts a large population of tissue-resident macrophages known as Kupffer cells (KCs). KCs are located in the hepatic sinusoids where they ensure key functions including blood immune surveillance. However, how KCs homeostasis is affected by the build-up of cholesterol-rich lipoproteins that occurs in the circulation during hypercholesterolemia remains unknown. Here, we found that embryo-derived KCs (EmKCs) accumulated large amounts of lipoprotein-derived cholesterol, in part through the scavenger receptor CD36, and massively expanded early after the induction of hypercholesterolemia. After this rapid adaptive response, EmKCs exhibited mitochondrial oxidative stress and their numbers gradually diminished while monocyte-derived KCs (MoKCs) with reduced cholesterol-loading capacities seeded the KC pool. Decreased proportion of EmKCs in the KC pool enhanced liver cholesterol content and exacerbated hypercholesterolemia, leading to accelerated atherosclerotic plaque development. Together, our data reveal that KC homeostasis is perturbed during hypercholesterolemia, which in turn alters the control of plasma cholesterol levels and increases atherosclerosis.