Phosphorylation by protein kinase C stabilizes ABCG1 and increases cholesterol efflux
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作者:
Watanabe, Taro
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Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, JapanKyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, Japan
Watanabe, Taro
[1
]
Kioka, Noriyuki
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Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, JapanKyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, Japan
Kioka, Noriyuki
[1
]
Ueda, Kazumitsu
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Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, Japan
Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Kyoto 6068501, JapanKyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, Japan
Ueda, Kazumitsu
[1
,2
]
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Matsuo, Michinori
[1
,3
]
机构:
[1] Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Cellular Biochem, Kyoto 6068502, Japan
[2] Kyoto Univ, Inst Integrated Cell Mat Sci WPI iCeMS, Kyoto 6068501, Japan
[3] Kyoto Womens Univ, Fac Home Econ, Dept Food & Nutr, Kyoto 6058501, Japan
ATP-binding cassette protein G1 (ABCG1) plays an important role in eliminating excess cholesterol from macrophages and in the formation of high-density lipoprotein (HDL), which contributes to the prevention and regression of atherosclerosis. The post-translational regulation of ABCG1 remains elusive, although phosphorylation by protein kinase A destabilizes ABCG1 proteins. We examined the phosphorylation of ABCG1 using HEK293 and Raw264.7 cells. ABCG1 phosphorylation was enhanced by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC) activator. PKC activation by TPA increased ABCG1 protein levels and promoted ABCG1-dependent cholesterol efflux to HDL. This activity was suppressed by Go6976, a PKC alpha/beta I inhibitor, suggesting that PKC activation stabilizes ABCG1. To confirm this, the degradation rate of ABCG1 was analysed; ABCG1 degradation was suppressed upon PKC activation, suggesting that PKC phosphorylation regulates ABCG1 levels. To confirm this involvement, we co-expressed ABCG1 and a constitutively active form of PKC alpha in HEK cells. ABCG1 was increased upon co-expression. These results suggest that PKC-mediated phosphorylation, probably PKC alpha, stabilizes ABCG1, consequently increasing ABCG1-mediated cholesterol efflux, by suppressing ABCG1 degradation. PKC activation could thus be a therapeutic target to suppress the development of atherosclerosis.
机构:
Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, JapanNiigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
Matsuo, Koji
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Yamamoto, Suguru
Wakamatsu, Takuya
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Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, JapanNiigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
Wakamatsu, Takuya
Takahashi, Yoshimitsu
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Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, JapanNiigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
Takahashi, Yoshimitsu
Kawamura, Kazuko
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Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, JapanNiigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
Kawamura, Kazuko
Kaneko, Yoshikatsu
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Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, JapanNiigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
Kaneko, Yoshikatsu
Goto, Shin
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Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, JapanNiigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
Goto, Shin
Kazama, Junichiro J.
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Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
Niigata Univ, Med & Dent Hosp, Div Blood Purificat Therapy, Niigata 9518520, JapanNiigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
Kazama, Junichiro J.
Narita, Ichiei
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Niigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, JapanNiigata Univ, Grad Sch Med & Dent Sci, Div Clin Nephrol & Rheumatol, Niigata 9518510, Japan
机构:
Univ Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Univ Kentucky, Med Ctr, Grad Ctr Nutr Sci, Saha Cardiovasc Res Ctr, Lexington, KY 40536 USA
Univ Kentucky, Med Ctr, Dept Vet Affairs, Lexington, KY 40536 USAUniv Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Bailey, William M.
Gizard, Florence
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Univ Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Univ Kentucky, Med Ctr, Grad Ctr Nutr Sci, Saha Cardiovasc Res Ctr, Lexington, KY 40536 USAUniv Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Gizard, Florence
Oslund, Rob C.
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Univ Washington, Dept Chem, Seattle, WA 98195 USAUniv Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Oslund, Rob C.
Gelb, Michael H.
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Univ Washington, Dept Chem, Seattle, WA 98195 USA
Univ Washington, Dept Biochem, Seattle, WA 98195 USAUniv Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Gelb, Michael H.
Bruemmer, Dennis
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Univ Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Univ Kentucky, Med Ctr, Grad Ctr Nutr Sci, Saha Cardiovasc Res Ctr, Lexington, KY 40536 USAUniv Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Bruemmer, Dennis
Webb, Nancy R.
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Univ Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA
Univ Kentucky, Med Ctr, Grad Ctr Nutr Sci, Saha Cardiovasc Res Ctr, Lexington, KY 40536 USA
Univ Kentucky, Med Ctr, Dept Vet Affairs, Lexington, KY 40536 USAUniv Kentucky, Med Ctr, Dept Internal Med, Div Endocrinol, Lexington, KY 40536 USA