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Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages.

Park SH, Paek JH, Shin D, Lee JY, Lim SS, Kang YH - Int. J. Mol. Med. (2015)

Bottom Line: Purple perilla, an annual herb in the mint family and its constituents, have been reported to exhibit antioxidant and cytostatic activity, as well as to exert anti-allergic effects.The liver X receptor (LXR) agonist, TO-091317, and the peroxisome proliferator-activated receptor (PPAR) agonist, pioglitazone, increased ABCA1 expression and treatment with 10 µg/ml PPE further enhanced this effect.The results from the present study demonstrate that PPE promotes cholesterol efflux from macrophages by activating the interaction of PPARγ-LXRα-ABC transporters.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea.

ABSTRACT
The cellular accumulation of cholesterol is critical in the development and progression of atherosclerosis. ATP-binding cassette (ABC) transporters play an essential role in mediating the efflux of excess cholesterol. In the current study, we investigated whether purple Perilla frutescens extracts (PPE) at a non-toxic concentration of 1-10 µg/ml stimulate the induction of the ABC transporters, ABCA1 and ABCG1, and cholesterol efflux from lipid-laden J774A.1 murine macrophages exposed to 50 ng/ml oxidized low-density lipoprotein (LDL). Purple perilla, an annual herb in the mint family and its constituents, have been reported to exhibit antioxidant and cytostatic activity, as well as to exert anti-allergic effects. Our results revealed that treatment with oxidized LDL for 24 h led to the accumulation of lipid droplets in the macrophages. PPE suppressed the oxidized LDL-induced foam cell formation by blocking the induction of scavenger receptor B1. However, PPE promoted the induction of the ABC transporters, ABCA1 and ABCG1, and subsequently accelerated cholesterol efflux from the lipid-loaded macrophages. The liver X receptor (LXR) agonist, TO-091317, and the peroxisome proliferator-activated receptor (PPAR) agonist, pioglitazone, increased ABCA1 expression and treatment with 10 µg/ml PPE further enhanced this effect. PPE did not induce LXRα and PPARγ expression per se, but enhanced their expression in the macrophages exposed to oxidized LDL. α-asarone was isolated from PPE and characterized as a major component enhancing the induction of ABCA1 and ABCG1 in macrophages exposed to oxidized LDL. α-asarone, but not β-asarone was effective in attenuating foam cell formation and enhancing cholesterol efflux, revealing an isomeric difference in their activity. The results from the present study demonstrate that PPE promotes cholesterol efflux from macrophages by activating the interaction of PPARγ-LXRα-ABC transporters.

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(A) Time course response of ABCA1 induction by TO-091317 and (B) upregulation of ABCA1 by purple Perilla frutescens extracts (PPE), and (C) enhancement of liver X receptor (LXR)α induction by PPE. J774A.1 murine macrophages were cultured with 1 μM TO-091317 or 50 μg/ml Cu2+-oxidized low-density lipoprotein (LDL) in the absence or presence of 1–10 μg/ml PPE. For the measurement of expression of (A and B) ABCA1 and (C) LXRα, total cell lysates were subjected to western blot analysis with a primary antibody against ABCA1 or LXRα. β-actin was used as an internal control. Bar graphs (means ± SEM, n=3) represent quantitative densitometric results of the upper bands. Bar graphs denoted without a common letter indicate significant difference, P<0.05.
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f3-ijmm-35-04-0957: (A) Time course response of ABCA1 induction by TO-091317 and (B) upregulation of ABCA1 by purple Perilla frutescens extracts (PPE), and (C) enhancement of liver X receptor (LXR)α induction by PPE. J774A.1 murine macrophages were cultured with 1 μM TO-091317 or 50 μg/ml Cu2+-oxidized low-density lipoprotein (LDL) in the absence or presence of 1–10 μg/ml PPE. For the measurement of expression of (A and B) ABCA1 and (C) LXRα, total cell lysates were subjected to western blot analysis with a primary antibody against ABCA1 or LXRα. β-actin was used as an internal control. Bar graphs (means ± SEM, n=3) represent quantitative densitometric results of the upper bands. Bar graphs denoted without a common letter indicate significant difference, P<0.05.

Mentions: We wished to confirm whether the upregulation of ABCA1 entails the nuclear induction of LXR, which was further accelerated by the administration of PPE. ABCA1 expression was highly induced within 4 h in the macrophages stimulated with the LXR agonist, TO-091317, at 1 μM and was sustained at high levels for up to 12 h (Fig. 3A). It should be noted that the induction of ABCA1 by TO-091317 was much more prominent than that induced by oxidized LDL (Fig. 3B). When the J774A.1 macrophages were treated with 1 μM TO-091317 for 8 h, the induction of ABCA1 was accelerated by treatment with 10 μg/ml PPE (Fig. 3B). In addition, the induction of LXRα by oxidized LDL was further enhanced in the PPE-treated macrophages (Fig. 3C). However, PPE per se did not induce nuclear LXRα expression (Fig. 3C). This indicated that the nuclear induction of LXRα by PPE in the presence of oxidized LDL appeared to be synergistic to that of TO-091317, which led to an increase in ABCA1 expression and cholesterol efflux.


Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages.

Park SH, Paek JH, Shin D, Lee JY, Lim SS, Kang YH - Int. J. Mol. Med. (2015)

(A) Time course response of ABCA1 induction by TO-091317 and (B) upregulation of ABCA1 by purple Perilla frutescens extracts (PPE), and (C) enhancement of liver X receptor (LXR)α induction by PPE. J774A.1 murine macrophages were cultured with 1 μM TO-091317 or 50 μg/ml Cu2+-oxidized low-density lipoprotein (LDL) in the absence or presence of 1–10 μg/ml PPE. For the measurement of expression of (A and B) ABCA1 and (C) LXRα, total cell lysates were subjected to western blot analysis with a primary antibody against ABCA1 or LXRα. β-actin was used as an internal control. Bar graphs (means ± SEM, n=3) represent quantitative densitometric results of the upper bands. Bar graphs denoted without a common letter indicate significant difference, P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356441&req=5

f3-ijmm-35-04-0957: (A) Time course response of ABCA1 induction by TO-091317 and (B) upregulation of ABCA1 by purple Perilla frutescens extracts (PPE), and (C) enhancement of liver X receptor (LXR)α induction by PPE. J774A.1 murine macrophages were cultured with 1 μM TO-091317 or 50 μg/ml Cu2+-oxidized low-density lipoprotein (LDL) in the absence or presence of 1–10 μg/ml PPE. For the measurement of expression of (A and B) ABCA1 and (C) LXRα, total cell lysates were subjected to western blot analysis with a primary antibody against ABCA1 or LXRα. β-actin was used as an internal control. Bar graphs (means ± SEM, n=3) represent quantitative densitometric results of the upper bands. Bar graphs denoted without a common letter indicate significant difference, P<0.05.
Mentions: We wished to confirm whether the upregulation of ABCA1 entails the nuclear induction of LXR, which was further accelerated by the administration of PPE. ABCA1 expression was highly induced within 4 h in the macrophages stimulated with the LXR agonist, TO-091317, at 1 μM and was sustained at high levels for up to 12 h (Fig. 3A). It should be noted that the induction of ABCA1 by TO-091317 was much more prominent than that induced by oxidized LDL (Fig. 3B). When the J774A.1 macrophages were treated with 1 μM TO-091317 for 8 h, the induction of ABCA1 was accelerated by treatment with 10 μg/ml PPE (Fig. 3B). In addition, the induction of LXRα by oxidized LDL was further enhanced in the PPE-treated macrophages (Fig. 3C). However, PPE per se did not induce nuclear LXRα expression (Fig. 3C). This indicated that the nuclear induction of LXRα by PPE in the presence of oxidized LDL appeared to be synergistic to that of TO-091317, which led to an increase in ABCA1 expression and cholesterol efflux.

Bottom Line: Purple perilla, an annual herb in the mint family and its constituents, have been reported to exhibit antioxidant and cytostatic activity, as well as to exert anti-allergic effects.The liver X receptor (LXR) agonist, TO-091317, and the peroxisome proliferator-activated receptor (PPAR) agonist, pioglitazone, increased ABCA1 expression and treatment with 10 µg/ml PPE further enhanced this effect.The results from the present study demonstrate that PPE promotes cholesterol efflux from macrophages by activating the interaction of PPARγ-LXRα-ABC transporters.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Nutrition, Hallym University, Chuncheon, Kangwon-do 200-702, Republic of Korea.

ABSTRACT
The cellular accumulation of cholesterol is critical in the development and progression of atherosclerosis. ATP-binding cassette (ABC) transporters play an essential role in mediating the efflux of excess cholesterol. In the current study, we investigated whether purple Perilla frutescens extracts (PPE) at a non-toxic concentration of 1-10 µg/ml stimulate the induction of the ABC transporters, ABCA1 and ABCG1, and cholesterol efflux from lipid-laden J774A.1 murine macrophages exposed to 50 ng/ml oxidized low-density lipoprotein (LDL). Purple perilla, an annual herb in the mint family and its constituents, have been reported to exhibit antioxidant and cytostatic activity, as well as to exert anti-allergic effects. Our results revealed that treatment with oxidized LDL for 24 h led to the accumulation of lipid droplets in the macrophages. PPE suppressed the oxidized LDL-induced foam cell formation by blocking the induction of scavenger receptor B1. However, PPE promoted the induction of the ABC transporters, ABCA1 and ABCG1, and subsequently accelerated cholesterol efflux from the lipid-loaded macrophages. The liver X receptor (LXR) agonist, TO-091317, and the peroxisome proliferator-activated receptor (PPAR) agonist, pioglitazone, increased ABCA1 expression and treatment with 10 µg/ml PPE further enhanced this effect. PPE did not induce LXRα and PPARγ expression per se, but enhanced their expression in the macrophages exposed to oxidized LDL. α-asarone was isolated from PPE and characterized as a major component enhancing the induction of ABCA1 and ABCG1 in macrophages exposed to oxidized LDL. α-asarone, but not β-asarone was effective in attenuating foam cell formation and enhancing cholesterol efflux, revealing an isomeric difference in their activity. The results from the present study demonstrate that PPE promotes cholesterol efflux from macrophages by activating the interaction of PPARγ-LXRα-ABC transporters.

Show MeSH
Related in: MedlinePlus