Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21
Konrad T. Sawicki, … , Perry J. Blackshear, Hossein Ardehali
Konrad T. Sawicki, … , Perry J. Blackshear, Hossein Ardehali
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e95948. https://doi.org/10.1172/jci.insight.95948.
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Research Article Metabolism

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21

Abstract

The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus–driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.

Authors

Konrad T. Sawicki, Hsiang-Chun Chang, Jason S. Shapiro, Marina Bayeva, Adam De Jesus, Brian N. Finck, Jason A. Wertheim, Perry J. Blackshear, Hossein Ardehali

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Figure 5

Fgf21 is a target of TTP.

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Fgf21 is a target of TTP. (A) mRNA expression of putative Ttp-targeted ...
(A) mRNA expression of putative Ttp-targeted hepatic secretory proteins in liver from WT and lsTtp-KO mouse fed normal chow (n = 10–12). (B) mRNA levels of putative Ttp-targeted hepatic secretory proteins in liver from WT and lsTtp-KO mouse fed HFD (n = 6–9). (C) Fasted lsTtp-KO mice have increased circulating FGF21 levels after 12 weeks of NC or HFD compared with WT mice (n = 6–14). (D) Genomic Evolutionary Rate Profiling (GERP) of AU-rich elements (AREs) in the FGF21 transcript demonstrates several evolutionarily conserved AREs. The numbers in the legend represent the nucleotide location of the ARE site with respect to the start of the coding region. (E) Fgf21 mRNA is stabilized in primary hepatocytes from lsTtp-KO compared with WT mice (n = 4). (F) TTP protein physically interacts with FGF21 mRNA as assessed by RNA co-IP (n = 3–6). (G) Human FGF21 3′-UTR-luciferase reporter construct signal is higher in Ttp-KO MEFs compared with WT MEFs (n = 6). (H) Overexpression of WT TTP, but not C124R mutant TTP, reduces luminescence signal of the human FGF21 3′-UTR-luciferase reporter construct (n = 5–6). (I) Deletion of ARE in human FGF21 3′-UTR-luciferase construct (ΔARE) abolishes the regulation by TTP overexpression (n = 8–15). Data presented as the relative luciferase activity in the presence of TTP overexpression for each construct. NC, normal chow; HFD, high-fat diet; EV, empty pMIR-REPORT vector; WT, WT human FGF21 3′-UTR-luciferase construct. Data are presented as mean ± SEM. *P < 0.05 by 1-way ANOVA with post hoc Fisher’s LSD test.