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Di Nunzio G, Hellberg S, Zhang Y, Ahmed O, Wang J, Zhang X, Björck HM, Chizh V, Schipper R, Aulin H, Francis R, Fagerberg L, Gisterå A, Metso J, Manfé V, Franco-Cereceda A, Eriksson P, Jauhiainen M, Hagberg CE, Olofsson PS, Malin SG
Nat Cardiovasc Res 3 (3) 356-371 [2024-03-00; online 2024-03-11]
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.
NGI Stockholm (Genomics Applications) [Service]
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 39196121
DOI 10.1038/s44161-024-00448-6
Crossref 10.1038/s44161-024-00448-6
pmc: PMC11358021
pii: 10.1038/s44161-024-00448-6