mTORC1 down-regulates cyclin-dependent kinase 8 (CDK8) and cyclin C (CycC)

Daorong Feng, Dou Yeon Youn, Xiaoping Zhao, Yanguang Gao, William J. Quinn, Alus M. Xiaoli, Yan Sun, Morris J. Birnbaum, Jeffrey E. Pessin, Fajun Yang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

In non-alcoholic fatty liver disease (NAFLD) and insulin resistance, hepatic de novo lipogenesis is often elevated, but the underlying mechanisms remain poorly understood. Recently, we show that CDK8 functions to suppress de novo lipogenesis. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a critical regulator of CDK8 and its activating partner CycC. Using pharmacologic and genetic approaches, we show that increased mTORC1 activation causes the reduction of the CDK8-CycC complex in vitro and in mouse liver in vivo. In addition, mTORC1 is more active in three mouse models of NAFLD, correlated with the lower abundance of the CDK8-CycC complex. Consistent with the inhibitory role of CDK8 on de novo lipogenesis, nuclear SREBP-1c proteins and lipogenic enzymes are accumulated in NAFLD models. Thus, our results suggest that mTORC1 activation in NAFLD and insulin resistance results in down-regulation of the CDK8-CycC complex and elevation of lipogenic protein expression.

Original languageEnglish (US)
Article numbere0126240
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 4 2015

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Cyclin-Dependent Kinase 8
Cyclin C
cyclin-dependent kinase
cyclins
Liver
Down-Regulation
fatty liver
Lipogenesis
lipogenesis
Disease Resistance
insulin resistance
disease resistance
Insulin Resistance
Chemical activation
Sterol Regulatory Element Binding Proteins
Insulin
Sterol Regulatory Element Binding Protein 1
liver
disease models
Nuclear Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

mTORC1 down-regulates cyclin-dependent kinase 8 (CDK8) and cyclin C (CycC). / Feng, Daorong; Youn, Dou Yeon; Zhao, Xiaoping; Gao, Yanguang; Quinn, William J.; Xiaoli, Alus M.; Sun, Yan; Birnbaum, Morris J.; Pessin, Jeffrey E.; Yang, Fajun.

In: PLoS One, Vol. 10, No. 6, e0126240, 04.06.2015.

Research output: Contribution to journalArticle

Feng, Daorong ; Youn, Dou Yeon ; Zhao, Xiaoping ; Gao, Yanguang ; Quinn, William J. ; Xiaoli, Alus M. ; Sun, Yan ; Birnbaum, Morris J. ; Pessin, Jeffrey E. ; Yang, Fajun. / mTORC1 down-regulates cyclin-dependent kinase 8 (CDK8) and cyclin C (CycC). In: PLoS One. 2015 ; Vol. 10, No. 6.
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AU - Gao, Yanguang

AU - Quinn, William J.

AU - Xiaoli, Alus M.

AU - Sun, Yan

AU - Birnbaum, Morris J.

AU - Pessin, Jeffrey E.

AU - Yang, Fajun

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