Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult
Hellberg, S.; Ahmed, O.; Zhang, Y.; Di Nunzio, G.; Bjorck, H. M.; Francis, R.; Fagerberg, L.; Gistera, A.; Zhang, X.; Metso, J.; Manfe, V.; Soto, Y.; Franco-Cereceda, A.; Eriksson, P.; Jauhiainen, M.; Olofsson, P. S.; Malin, S. G.
Show abstract
Apolipoprotein-B (APOB) containing lipoproteins are causative for atherosclerotic cardiovascular disease. Whether the vasculature is the initial responding site or if atherogenic-dyslipidemia effects other organs simultaneously is unknown. We set out to discover how the liver responds to a dyslipidemic insult through the creation of inducible mouse models based on human familial hypercholesterolemia mutations and in vivo tracing of APOB. An acute transition to atherogenic APOB-lipoprotein plasma levels resulted in rapid accumulation of triglycerides and cholesterol in the liver. Single cell RNA-seq and flow cytometry disclosed that multiple immune cells have the ability to engulf APOB-lipoproteins. However bulk RNA-seq of the liver revealed an inflammatory Kupffer cell-specific transcriptional program that could not be activated by a western diet alone. Depletion of Kupffer cells through clodronate liposomes or CD8 T cell targeting rapidly raised plasma lipoprotein levels, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins, whilst simultaneously secreting pro-atherosclerotic factors into plasma. Our results place Kupffer cells as a key gateway in organizing systemic responses at the initiation of atherosclerosis.
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