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Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult

ABSTRACT: Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is 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-seq revealed an 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, whilst 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE254879 | GEO | 2024/02/05

REPOSITORIES: GEO

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Project description:Beneficial effects of long-chain omega-3 polyunsaturated fatty acids (n-3 FAs) are generally well-known from epidemiological studies, but the various mechanisms of action are not completely clarified. Regulation of gene expression is one known mechanism of action, but only very limited data of regulated pathways in humans after n-3 FA supplementation are available. Up to now, no studies compared gene expression changes after n-3 FA supplementation between normolipidemic and dyslipidemic subjects. Therefore, the aim of this study was to investigate the effects of n-3 FA administration on whole genome expression profiles in the blood of normo- and dyslipidemic subjects. We conducted an intervention study with normo- and dyslipidemic men aged between 29 and 51 years, which were subdivided into four groups with a balanced age distribution and randomized to either six fish oil capsules per day providing 1.5 g docosahexaenoic acid and 1.0 g eicosapentaenoic acid or corn oil capsules rich in linoleic acid per day for a period of 12 weeks. Venous blood samples were collected at baseline as well as after 4 hours, 1 week and 12 weeks of supplementation. For each investigation time point, the samples of each group were pooled together to minimize inter-individual variability. All subjects have successfully completed the study, but for the microarray experiments, nine subject samples were excluded. Therefore, the microarray experiments are based on the following group characteristics: normolipidemic fish oil group (FO-N): pool of nine RNAs from normolipidemic subjects supplemented with fish oil; normolipidemic corn oil group (CO-N): pool of six RNAs from normolipidemic subjects supplemented with corn oil; dyslipidemic corn oil group (CO-D): pool of eight RNAs from dyslipidemic subjects supplemented with corn oil; dyslipidemic fish oil group (FO-D): pool of nine RNAs from dyslipidemic subjects supplemented with fish oil. The twenty normolipidemic and the twenty dyslipidemic subjects were subdivided into two groups. Thus, a total of four groups with ten men per group passed through the study. To realize a comparable mean age between groups, the formation of groups was performed by stratified allocation according to subject's age. The four study groups were randomly assigned to different study products by an uninvolved collaborator. Subjects ingested either six FO or six corn oil (CO) capsules per day for a period of twelve weeks. The daily n-3 PUFA intake via FO capsules was 2.7 g (1.14 g DHA and 1.56 g EPA). The predominant FA of the CO capsules was the omega-6 (n-6) PUFA linoleic acid (LA, 18:2n-6). Thus, the daily LA intake via CO capsules was 3.05 g LA. The subjects were instructed to ingest the capsules together with food, three in the morning and three in the evening, and to maintain their usual exercise and dietary habits throughout the intervention time. As an exception, at the first intervention day, all six capsules were ingested at the same time in the morning after a standardised breakfast. During each visit, fasting blood samples were collected by venepuncture. Additionally, participants completed a questionnaire to obtain information about changes in medication, dietary (e.g., changes in weekly fish intake, preferred fish dishes or species, respectively) and lifestyle habits (e.g., physical activity), as well as the tolerability of the capsules. This record summarizes the results of 16 microarrays. The samples originate from whole blood of normo- and dyslipidemic subjects supplemented with either fish oil or corn oil for 4 h, 1 week and 12 weeks. Microarrays were hybridized in a loop design with one common reference using a dye-swap approach.

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Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult

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