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Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7973-7981. doi: 10.1073/pnas.1816023116. Epub 2019 Mar 29.

Hepatic posttranscriptional network comprised of CCR4-NOT deadenylase and FGF21 maintains systemic metabolic homeostasis.

Author information

1
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; moritam@uthscsa.edu tadashi.yamamoto@oist.jp nahum.sonenberg@mcgill.ca.
2
Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.
3
Institute of Resource Development and Analysis, Kumamoto University, 860-0811 Kumamoto, Japan.
4
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada.
5
Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
6
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229.
7
Department of Oncology-Pathology, Scilifelab, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
8
Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045 Kanagawa, Japan.
9
Research Centre, Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada.
10
Department of Human Genetics, McGill University, Montreal, QC H3A 2T5, Canada.
11
Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, 904-0495 Okinawa, Japan.
12
Laboratories for Animal Resource Development and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, 650-0047 Hyogo, Japan.
13
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 860-8556 Kumamoto, Japan.
14
Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H2W 1S6, Canada.
15
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
16
Laboratory of Cell Systems, Institute for Protein Research, Osaka University, Suita, 565-0871 Osaka, Japan.
17
Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, 904-0495 Okinawa, Japan; moritam@uthscsa.edu tadashi.yamamoto@oist.jp nahum.sonenberg@mcgill.ca.
18
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; moritam@uthscsa.edu tadashi.yamamoto@oist.jp nahum.sonenberg@mcgill.ca.

Abstract

Whole-body metabolic homeostasis is tightly controlled by hormone-like factors with systemic or paracrine effects that are derived from nonendocrine organs, including adipose tissue (adipokines) and liver (hepatokines). Fibroblast growth factor 21 (FGF21) is a hormone-like protein, which is emerging as a major regulator of whole-body metabolism and has therapeutic potential for treating metabolic syndrome. However, the mechanisms that control FGF21 levels are not fully understood. Herein, we demonstrate that FGF21 production in the liver is regulated via a posttranscriptional network consisting of the CCR4-NOT deadenylase complex and RNA-binding protein tristetraprolin (TTP). In response to nutrient uptake, CCR4-NOT cooperates with TTP to degrade AU-rich mRNAs that encode pivotal metabolic regulators, including FGF21. Disruption of CCR4-NOT activity in the liver, by deletion of the catalytic subunit CNOT6L, increases serum FGF21 levels, which ameliorates diet-induced metabolic disorders and enhances energy expenditure without disrupting bone homeostasis. Taken together, our study describes a hepatic CCR4-NOT/FGF21 axis as a hitherto unrecognized systemic regulator of metabolism and suggests that hepatic CCR4-NOT may serve as a target for devising therapeutic strategies in metabolic syndrome and related morbidities.

KEYWORDS:

CCR4–NOT; FGF21; deadenylase; hepatokine; metabolic syndrome

PMID:
30926667
PMCID:
PMC6475422
[Available on 2019-09-29]
DOI:
10.1073/pnas.1816023116

Conflict of interest statement

The authors declare no conflict of interest.

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