The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase

被引：257

作者：

White, Phillip J. ^{[1
,2
,3
,4
]}

McGarrah, Robert W. ^{[1
,2
,3
,4
]}

Grimsrud, Paul A. ^{[1
,2
]}

Tso, Shih-Chia ^{[5
]}

Yang, Wen-Hsuan ^{[1
,2
]}

Haldeman, Jonathan M. ^{[1
,2
]}

Grenier-Larouche, Thomas ^{[1
,2
]}

An, Jie ^{[1
,2
]}

Lapworth, Amanda L. ^{[1
,2
]}

Astapova, Inna ^{[1
,2
,3
,4
]}

Hannou, Sarah A. ^{[1
,2
]}

George, Tabitha ^{[1
,2
]}

Arlotto, Michelle ^{[1
,2
]}

Olson, Lyra B. ^{[1
,2
]}

Lai, Michelle ^{[6
]}

Zhang, Guo-Fang ^{[1
,2
,3
,4
]}

Ilkayeva, Olga ^{[1
,2
]}

Herman, Mark A. ^{[1
,2
,3
,4
]}

Wynn, R. Max ^{[5
]}

Chuang, David T. ^{[5
]}

Newgard, Christopher B. ^{[1
,2
,3
,4
]}

机构：

[1] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, 300 North Duke St, Durham, NC 27701 USA

[2] Duke Univ, Med Ctr, Duke Mol Physiol Inst, 300 North Duke St, Durham, NC 27701 USA

[3] Dept Med & Pharmacol, Durham, NC 27701 USA

[4] Dept Canc Biol, Durham, NC 27701 USA

[5] Univ Texas Southwestern Med Ctr, Dept Biochem, Dallas, TX 75390 USA

[6] Beth Israel Deaconess Med Ctr, Div Gastroenterol, Boston, MA 02215 USA

来源：

CELL METABOLISM | 2018年 / 27卷 / 06期

关键词：

KETOACID DEHYDROGENASE KINASE; ACETYL-COA CARBOXYLASE; CHAIN AMINO-ACIDS; STIMULATED INSULIN-SECRETION; PROTEIN-KINASE; ISOLATED ADIPOCYTES; GLUCOSE-PRODUCTION; DEFICIENT MICE; FATTY-ACID; RAT-LIVER;

D O I：

10.1016/j.cmet.2018.04.015

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-beta transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK: PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity.

引用

页码：1281 / +

页数：20

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