Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes

被引：16
|
作者：
Nishi, Kiyoto [1 ,3 ]
Yoshii, Akira [1 ]
Abell, Lauren [1 ]
Zhou, Bo [1 ]
Frausto, Ricardo [4 ]
Ritterhoff, Julia [1 ]
McMillen, Timothy S. [1 ]
Sweet, Ian [2 ]
Wang, Yibin [4 ,5 ]
Gao, Chen [4 ,6 ]
Tian, Rong [1 ]
机构：
[1] Univ Washington, Mitochondria & Metab Ctr, Dept Anesthesiol & Pain Med, 850 Republican St, Seattle, WA 98109 USA
[2] Univ Washington, Med Diabet Inst, 750 Republican St, Seattle, WA 98109 USA
[3] Shiga Univ Med Sci, Dept Pharmacol, Otsu, Shiga 5202182, Japan
[4] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Cardiovasc Res Labs, Los Angeles, CA 90095 USA
[5] Duke NUS Sch Med, Signature Program Cardiovasc & Metab Dis, Singapore, Singapore
[6] Univ Cincinnati, Coll Med, Dept Pharmacol & Syst Physiol, Cincinnati, OH 45267 USA
来源：
CELL REPORTS | 2023年 / 42卷 / 06期
基金：
美国国家卫生研究院;
关键词：
AMINO-ACIDS; INSULIN-RESISTANCE; GLUCOSE-METABOLISM; CATABOLISM; TRANSPORT; HEART;
D O I：
10.1016/j.celrep.2023.112641
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accu-mulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k-deficient mice and can be restored with pharmacolog-ical activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism.
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页数：18
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