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

被引：24

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.

引用

页数：18