Anti-Inflammatory Effects of Dietary Plant Stanol Supplementation Are Largely Dependent on the Intake of Cholesterol in a Mouse Model of Metabolic Inflammation

Abstract

The prevalence of metabolic disorders characterized by chronic inflammation has been on a sharp rise for decades. As such, tools that address metabolic and inflammatory dysregulation are of great importance. Plant stanols are well-known for reducing intestinal cholesterol absorption and may also have direct anti-inflammatory effects. In this study, our aim was to investigate to what extent the benefits of dietary plant stanol supplementation depend on dietary cholesterol intake in an experimental mouse model for cholesterol-induced metabolic inflammation. Here, we used Ldlr−/− mice transplanted with Npc1nih-derived bone marrow, featuring feature bone marrow-derived immune cells characterized by chronic inflammation induced by lysosomal lipid accumulation. Npc1nih- and Npc1wt-transplanted mice were placed on either a high fat, high cholesterol (HFC) or on a chow diet low in cholesterol, with or without 2% plant stanols supplementation. At the end of the study, the metabolic and inflammatory status of the mice was analyzed. Plant stanol supplementation to the HFC diet reduced liver cholesterol levels and improved lipid metabolism and liver inflammation, particularly in Npc1nih-tp mice. In contrast, plant stanol supplementation to the chow diet did not significantly improve the aforementioned parameters, though similar reductive trends to those in the HFC diet setting were observed regarding liver cholesterol accumulation and liver inflammatory markers. The effects of dietary plant stanol supplementation on dietary cholesterol-induced inflammation are largely dependent on dietary cholesterol intake. Future research should verify whether other models of metabolic inflammation exhibit similar stanol-related effects on inflammation.

Elevated granulocyte-colony stimulating factor and hematopoietic stem cell mobilization in Niemann-Pick type C1 disease

“…While elevated G-CSF may be disadvantageous in terms of its contribution to splenomegaly, G-CSF stimulates neurogenesis ( 58 ), which could counteract the neurodegenerative disease in NPC1 patients. Recent studies have shown that stanol supplementation reduces inflammation in mice with the Npc1 loss-of-function mutation, including a decrease in inflammatory blood monocytes and hepatic neutrophil infiltration ( 32 , 59 ), perhaps because of reducing 7-KC. Injections with 2-hydroxypropyl-β-cyclodextrin are currently in phase 2/3 clinical trials for NPC1 disease (NCT02534844) and improve liver function, delay neurodegeneration, and increase life span of Npc1 −/− mice ( 60 , 61 , 62 ) but do not decrease splenomegaly in WTD-fed Ldlr −/− mice transplanted with BM from mice with Npc1 loss-of-function ( 63 ).…”

Pro-Inflammatory Implications of 2-Hydroxypropyl-β-cyclodextrin Treatment

“…Notably, while neutrophils generally constitute the major immune cell population under inflammatory conditions, in the current study we only focused on the effect of CD on macrophages. This choice is based on previous findings by our group that demonstrate macrophages to be the most important immune cell in the in vivo model here described (as evidenced by changes in hematopoiesis ( 38 ) and organ-specific inflammation ( 22 )). Nevertheless, as neutrophil aberrations have also been described in NPC1 disease ( 39 ), future research should further explore the involvement of neutrophils in CD-induced inflammatory responses in a metabolic inflammatory context.…”

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“…Notably, while neutrophils generally constitute the major immune cell population under inflammatory conditions, in the current study we only focused on the effect of CD on macrophages. This choice is based on previous findings by our group that demonstrate macrophages to be the most important immune cell in the in vivo model here described (as evidenced by changes in hematopoiesis (38) and organspecific inflammation (22)). Nevertheless, as neutrophil aberrations have also been described in NPC1 disease (39), future research should further explore the involvement of neutrophils in CD-induced inflammatory responses in a metabolic inflammatory context.…”