👤 Linn Fagerberg

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initially responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis. Show less

In this study we have used mass spectrometry in order to characterize the HDL lipidome in three groups of women from the DIWA cohort; one control group, plus two groups with type 2 diabetes with insulin resistance; one dyslipidemic and one normolipidemic. The aim was to investigate whether dyslipidemia is required in addition to insulin resistance for the occurrence of an altered HDL lipidome, which in turn might impact HDL functionality. The dyslipidemic type 2 diabetic subjects were distinguished by obesity, hypertriglyceridemia with elevated apoC3, low HDL-cholesterol and chronic low grade inflammation. In a stepwise multivariate linear regression analysis, including biomarkers of dyslipidemia and insulin resistance as independent variables, only dyslipidemia showed a significant correlation with HDL lipid classes. Small HDL-particles predominated in dyslipidemic subjects in contrast to the normolipidemic diabetic and control groups, and were enriched in lysophosphatidylcholine (+13%), a product of proinflammatory phospholipases, and equally in two core lipids, palmitate-rich triacylglycerols and diacylglycerols (+77 %), thereby reflecting elevated CETP activity. Dyslipidemic small HDL particles were further distinguished not only as the primary carrier of ceramides, which promote inflammation and insulin resistance, but also by a subnormal plasmalogen/apoAI ratio, consistent with elevated oxidative stress typical of type 2 diabetes. From these data we conclude that in type 2 diabetes, dyslipidemia predominates relative to hyperglycemia for the occurrence of an altered HDL lipidome. Furthermore, dyslipidemia alters the cargo of bioactive lipids, with implications for HDL function. Show less