Limits...
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.

Show MeSH

Related in: MedlinePlus

Hepatic non-cholesterol sterol concentrations.Hepatic concentrations of (A) campesterol, (B) sitosterol, (C) campestanol and (D) sitostanol were measured. To analyze endogenous cholesterol synthesis, hepatic (E) lathosterol and (F) desmosterol were measured. All values are shown as absolute concentrations (ng/mg tissue). n = 10 per group. *P<0.05, ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4214692&req=5

pone-0110758-g006: Hepatic non-cholesterol sterol concentrations.Hepatic concentrations of (A) campesterol, (B) sitosterol, (C) campestanol and (D) sitostanol were measured. To analyze endogenous cholesterol synthesis, hepatic (E) lathosterol and (F) desmosterol were measured. All values are shown as absolute concentrations (ng/mg tissue). n = 10 per group. *P<0.05, ***P<0.001.

Mentions: Upon consumption, it is well accepted that plant sterols and stanols are distributed into different tissues, including the liver [7]. As shown in Figure 6A, hepatic campesterol concentrations increased upon plant sterol feeding and slightly decreased after plant stanol ester feeding. Remarkably, there was no increase in hepatic sitosterol concentrations after plant sterol ester feeding as compared to chow, whereas the expected reduction in hepatic sitosterol concentrations after plant stanol ester feeding was evident (Figure 6B). Regarding hepatic plant stanol concentrations, there was a significant increase in campestanol and sitostanol concentrations after plant stanol ester feeding (Figure 6C, D). This data clearly indicates that hepatic plant sterol and stanol concentrations increase upon consumption and might in theory have local effects. Finally, feeding the HFD severely elevated hepatic lathosterol as well as desmosterol concentrations suggesting a strong increase in endogenous cholesterol synthesis (Figure 6E, F). The recent observations that desmosterol is an important regulator of inflammatory processes in macrophages [6] might also suggest a local effect on inflammation in the Kupffer cells. Moreover, as compared to the HFD, adding plant sterol or stanol esters to the diet lowered hepatic lathosterol and desmosterol concentrations, an indication of a lower endogenous cholesterol synthesis. Finally, hepatic cholestanol concentrations were lowered in the HFD + stanol and sterol ester groups as compared to the HFD group alone (data not shown), indicative of a lowered intestinal cholesterol absorption. Next to that, the expression of enzymes regulating endogenous cholesterol synthesis either via the Kandutsch-Russell pathway or the Bloch pathway suggested increased synthesis in the stanol and sterol ester conditions. As compared to the HFD fed mice, the expression of Cyp51 and LSS was higher both in the sterol and stanol ester condition (Figure S1A, B). Further, the expression of Dhcr24 was increased in the sterol ester condition and the expression of Dhcr7 was increased in the stanol ester condition compared to mice upon HFD (Figure S1C, D). Interestingly, the HFD condition did not show significant differences in expression of these 4 genes compared to chow condition (Figure S1A–D).


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)

Hepatic non-cholesterol sterol concentrations.Hepatic concentrations of (A) campesterol, (B) sitosterol, (C) campestanol and (D) sitostanol were measured. To analyze endogenous cholesterol synthesis, hepatic (E) lathosterol and (F) desmosterol were measured. All values are shown as absolute concentrations (ng/mg tissue). n = 10 per group. *P<0.05, ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214692&req=5

pone-0110758-g006: Hepatic non-cholesterol sterol concentrations.Hepatic concentrations of (A) campesterol, (B) sitosterol, (C) campestanol and (D) sitostanol were measured. To analyze endogenous cholesterol synthesis, hepatic (E) lathosterol and (F) desmosterol were measured. All values are shown as absolute concentrations (ng/mg tissue). n = 10 per group. *P<0.05, ***P<0.001.
Mentions: Upon consumption, it is well accepted that plant sterols and stanols are distributed into different tissues, including the liver [7]. As shown in Figure 6A, hepatic campesterol concentrations increased upon plant sterol feeding and slightly decreased after plant stanol ester feeding. Remarkably, there was no increase in hepatic sitosterol concentrations after plant sterol ester feeding as compared to chow, whereas the expected reduction in hepatic sitosterol concentrations after plant stanol ester feeding was evident (Figure 6B). Regarding hepatic plant stanol concentrations, there was a significant increase in campestanol and sitostanol concentrations after plant stanol ester feeding (Figure 6C, D). This data clearly indicates that hepatic plant sterol and stanol concentrations increase upon consumption and might in theory have local effects. Finally, feeding the HFD severely elevated hepatic lathosterol as well as desmosterol concentrations suggesting a strong increase in endogenous cholesterol synthesis (Figure 6E, F). The recent observations that desmosterol is an important regulator of inflammatory processes in macrophages [6] might also suggest a local effect on inflammation in the Kupffer cells. Moreover, as compared to the HFD, adding plant sterol or stanol esters to the diet lowered hepatic lathosterol and desmosterol concentrations, an indication of a lower endogenous cholesterol synthesis. Finally, hepatic cholestanol concentrations were lowered in the HFD + stanol and sterol ester groups as compared to the HFD group alone (data not shown), indicative of a lowered intestinal cholesterol absorption. Next to that, the expression of enzymes regulating endogenous cholesterol synthesis either via the Kandutsch-Russell pathway or the Bloch pathway suggested increased synthesis in the stanol and sterol ester conditions. As compared to the HFD fed mice, the expression of Cyp51 and LSS was higher both in the sterol and stanol ester condition (Figure S1A, B). Further, the expression of Dhcr24 was increased in the sterol ester condition and the expression of Dhcr7 was increased in the stanol ester condition compared to mice upon HFD (Figure S1C, D). Interestingly, the HFD condition did not show significant differences in expression of these 4 genes compared to chow condition (Figure S1A–D).

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