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Protective role of plant sterol and stanol esters in liver inflammation: insights from mice and humans.

Plat J, Hendrikx T, Bieghs V, Jeurissen ML, Walenbergh SM, van Gorp PJ, De Smet E, Konings M, Vreugdenhil AC, Guichot YD, Rensen SS, Buurman WA, Greve JW, Lütjohann D, Mensink RP, Shiri-Sverdlov R - PLoS ONE (2014)

Bottom Line: Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation.Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers.In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Biology, School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, the Netherlands.

ABSTRACT
The inflammatory component of non-alcoholic steatohepatitis (NASH) can lead to irreversible liver damage. Therefore there is an urgent need to identify novel interventions to combat hepatic inflammation. In mice, omitting cholesterol from the diet reduced hepatic inflammation. Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation. Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers. Finally, adding sterol/stanol esters lowered hepatic concentrations of cholesterol precursors lathosterol and desmosterol in mice, which were highly elevated in the HFD group similarly as observed in severely obese patients with NASH. In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation. This highly interesting observation that plant sterol/stanol ester consumption leads to complete inhibition of HFD-induced liver inflammation opens new venues in the treatment and prevention of hepatic inflammation.

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Effect of plant stanols on macrophages in vitro.Changes in Tnf-α concentrations in supernatant and LXR target gene expression of bone marrow derived macrophages after incubation with sitostanol (0.6 and 1.2 µm) or desmosterol (0.25, 0.5 and 1.0 µm) and 4 h LPS stimulation. (A) Tnf-α concentrations, (B) LXRα mRNA, (C) Abca1 mRNA, and (D) Abcg1 mRNA expression after sitostanol exposure, (E) Tnf-α mRNA, (F) LXRα mRNA, (G) Abca1 mRNA, and (H) Abcg1 mRNA expression after desmosterol exposure. Data were set relative to cells incubated with cyclodextrin (carrier control). *P<0.05; **P<0.01; ***P<0.001.
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pone-0110758-g007: Effect of plant stanols on macrophages in vitro.Changes in Tnf-α concentrations in supernatant and LXR target gene expression of bone marrow derived macrophages after incubation with sitostanol (0.6 and 1.2 µm) or desmosterol (0.25, 0.5 and 1.0 µm) and 4 h LPS stimulation. (A) Tnf-α concentrations, (B) LXRα mRNA, (C) Abca1 mRNA, and (D) Abcg1 mRNA expression after sitostanol exposure, (E) Tnf-α mRNA, (F) LXRα mRNA, (G) Abca1 mRNA, and (H) Abcg1 mRNA expression after desmosterol exposure. Data were set relative to cells incubated with cyclodextrin (carrier control). *P<0.05; **P<0.01; ***P<0.001.

Mentions: To investigate whether plant stanols may affect Kupffer cells directly independent of changes in cholesterol or lipid concentrations and the presence of communicating hepatocytes, isolated bone-marrow derived macrophages were incubated with LPS and plant stanols, and levels of Tnf-α secreted in culture medium were measured. Macrophages incubated with plant stanols produced less Tnf-α after exposure to sitostanol, both after 0.6 and 1.2 µm concentrations as compared to cyclodextrin (carrier control) (Figure 7A). On the other hand, there was no significant change in the mRNA expression of liver X receptor alpha (LXRα), a transcription factor important for cholesterol homeostasis and lipid transporter genes Abca1 and Abcg1 (Figure 7B–D). Since we observed the strong increase in desmosterol concentrations in the livers of the HFD mice, we also cultured the isolated bone-marrow derived macrophages with desmosterol to better understand the effect of these changes. In contrast to sitostanol, supplying desmosterol did not have an effect on the expression of Tnf-α (Figure 7E) and cellular Mcp-1 production (data not shown) but instead increased the expression of LXRα and the LXR target genes Abca1 and Abcg1 (Figure 7F–H) indicating increased cholesterol efflux. Altogether, these data suggest that (1) plant stanols could directly affect inflammation in macrophages independent of lipid and/or cholesterol metabolism and (2) the increased desmosterol concentration in the HFD condition serves to remove excess cellular cholesterol, a situation that was absent in the HDF + plant sterol or stanol ester condition.


Protective role of plant sterol and stanol esters in liver inflammation: insights from mice and humans.

Plat J, Hendrikx T, Bieghs V, Jeurissen ML, Walenbergh SM, van Gorp PJ, De Smet E, Konings M, Vreugdenhil AC, Guichot YD, Rensen SS, Buurman WA, Greve JW, Lütjohann D, Mensink RP, Shiri-Sverdlov R - PLoS ONE (2014)

Effect of plant stanols on macrophages in vitro.Changes in Tnf-α concentrations in supernatant and LXR target gene expression of bone marrow derived macrophages after incubation with sitostanol (0.6 and 1.2 µm) or desmosterol (0.25, 0.5 and 1.0 µm) and 4 h LPS stimulation. (A) Tnf-α concentrations, (B) LXRα mRNA, (C) Abca1 mRNA, and (D) Abcg1 mRNA expression after sitostanol exposure, (E) Tnf-α mRNA, (F) LXRα mRNA, (G) Abca1 mRNA, and (H) Abcg1 mRNA expression after desmosterol exposure. Data were set relative to cells incubated with cyclodextrin (carrier control). *P<0.05; **P<0.01; ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4214692&req=5

pone-0110758-g007: Effect of plant stanols on macrophages in vitro.Changes in Tnf-α concentrations in supernatant and LXR target gene expression of bone marrow derived macrophages after incubation with sitostanol (0.6 and 1.2 µm) or desmosterol (0.25, 0.5 and 1.0 µm) and 4 h LPS stimulation. (A) Tnf-α concentrations, (B) LXRα mRNA, (C) Abca1 mRNA, and (D) Abcg1 mRNA expression after sitostanol exposure, (E) Tnf-α mRNA, (F) LXRα mRNA, (G) Abca1 mRNA, and (H) Abcg1 mRNA expression after desmosterol exposure. Data were set relative to cells incubated with cyclodextrin (carrier control). *P<0.05; **P<0.01; ***P<0.001.
Mentions: To investigate whether plant stanols may affect Kupffer cells directly independent of changes in cholesterol or lipid concentrations and the presence of communicating hepatocytes, isolated bone-marrow derived macrophages were incubated with LPS and plant stanols, and levels of Tnf-α secreted in culture medium were measured. Macrophages incubated with plant stanols produced less Tnf-α after exposure to sitostanol, both after 0.6 and 1.2 µm concentrations as compared to cyclodextrin (carrier control) (Figure 7A). On the other hand, there was no significant change in the mRNA expression of liver X receptor alpha (LXRα), a transcription factor important for cholesterol homeostasis and lipid transporter genes Abca1 and Abcg1 (Figure 7B–D). Since we observed the strong increase in desmosterol concentrations in the livers of the HFD mice, we also cultured the isolated bone-marrow derived macrophages with desmosterol to better understand the effect of these changes. In contrast to sitostanol, supplying desmosterol did not have an effect on the expression of Tnf-α (Figure 7E) and cellular Mcp-1 production (data not shown) but instead increased the expression of LXRα and the LXR target genes Abca1 and Abcg1 (Figure 7F–H) indicating increased cholesterol efflux. Altogether, these data suggest that (1) plant stanols could directly affect inflammation in macrophages independent of lipid and/or cholesterol metabolism and (2) the increased desmosterol concentration in the HFD condition serves to remove excess cellular cholesterol, a situation that was absent in the HDF + plant sterol or stanol ester condition.

Bottom Line: Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation.Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers.In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Biology, School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, the Netherlands.

ABSTRACT
The inflammatory component of non-alcoholic steatohepatitis (NASH) can lead to irreversible liver damage. Therefore there is an urgent need to identify novel interventions to combat hepatic inflammation. In mice, omitting cholesterol from the diet reduced hepatic inflammation. Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation. Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers. Finally, adding sterol/stanol esters lowered hepatic concentrations of cholesterol precursors lathosterol and desmosterol in mice, which were highly elevated in the HFD group similarly as observed in severely obese patients with NASH. In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation. This highly interesting observation that plant sterol/stanol ester consumption leads to complete inhibition of HFD-induced liver inflammation opens new venues in the treatment and prevention of hepatic inflammation.

Show MeSH
Related in: MedlinePlus