Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice
Neha Bhat, … , Gerald I. Shulman, Arya Mani
Neha Bhat, … , Gerald I. Shulman, Arya Mani
Published December 2, 2021
Citation Information: J Clin Invest. 2022;132(3):e153724. https://doi.org/10.1172/JCI153724.
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Research Article Hepatology Metabolism

Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice

Abstract

Mutations in Dyrk1b are associated with metabolic syndrome and nonalcoholic fatty liver disease in humans. Our investigations showed that DYRK1B levels are increased in the liver of patients with nonalcoholic steatohepatitis (NASH) and in mice fed with a high-fat, high-sucrose diet. Increasing Dyrk1b levels in the mouse liver enhanced de novo lipogenesis (DNL), fatty acid uptake, and triacylglycerol secretion and caused NASH and hyperlipidemia. Conversely, knockdown of Dyrk1b was protective against high-calorie-induced hepatic steatosis and fibrosis and hyperlipidemia. Mechanistically, Dyrk1b increased DNL by activating mTORC2 in a kinase-independent fashion. Accordingly, the Dyrk1b-induced NASH was fully rescued when mTORC2 was genetically disrupted. The elevated DNL was associated with increased plasma membrane sn-1,2-diacylglyerol levels and increased PKCε-mediated IRKT1150 phosphorylation, which resulted in impaired activation of hepatic insulin signaling and reduced hepatic glycogen storage. These findings provide insights into the mechanisms that underlie Dyrk1b-induced hepatic lipogenesis and hepatic insulin resistance and identify Dyrk1b as a therapeutic target for NASH and insulin resistance in the liver.

Authors

Neha Bhat, Anand Narayanan, Mohsen Fathzadeh, Mario Kahn, Dongyan Zhang, Leigh Goedeke, Arpita Neogi, Rebecca L. Cardone, Richard G. Kibbey, Carlos Fernandez-Hernando, Henry N. Ginsberg, Dhanpat Jain, Gerald I. Shulman, Arya Mani

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Figure 5

Dyrk1b increases FA uptake in the hepatocytes.

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Dyrk1b increases FA uptake in the hepatocytes. (A–H) Representative conf...
(A–H) Representative confocal images from littermate controls and Dyrk1b–/– hepatocytes at indicated time points after addition of BODIPY-FA; n = 5 mice each genotype, n = 4 technical replicates. (I) Quantification of intracellular fluorescence in controls and Dyrk1b–/– hepatocytes measured by the microplate reader after cell lysis at the indicated time points. The background fluorescence (prior to addition of BODIPY-FA) was subtracted and normalized to the total protein content. Unpaired t test, 2-sided, n = 5 mice each genotype, n = 4 technical replicates. (J–L) Representative confocal images showing BODIPY-FA uptake 1 minute after addition in Dyrk1b–/– hepatocytes transduced with AAV8 containing empty vector (AAVcontrol) or Dyrk1bWT or Dyrk1bkin.def virus, at an MOI of 60. The FA uptake experiment was performed 72 hours after virus transduction, to allow for sufficient transcription. n = 2 mice each condition, n = 4 technical replicates. (M) Quantification of intracellular fluorescence, in the indicated genotypes; 1-way ANOVA, Tukey’s post hoc test. White arrows indicate the intracellular fluorescence detected by BODIPY-FA. Scale bars: 150 μm. **P ≤ 0.01, ***P ≤ 0.001.