Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice
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
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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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 8

Knockout of Rictor, an obligate mTORC2 subunit, rescues steatohepatitis in Dyrk1bAAV-WT liver.

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Knockout of Rictor, an obligate mTORC2 subunit, rescues steatohepatitis ...
(A–H) ORO staining in the liver of mice fed with CD (A–D), n > 8 each, or HCD (E–H), n > 6 mice each. (I–L) CD68 (red), SMA (green), F4/80 (white) costaining in the designated mice fed with HCD for 5 months to induce inflammation; n > 6 mice each. (M) Hepatic TAG normalized to total protein in the designated mice fed with CD. The data from Figure 2E are repeated to display all the controls together. n > 6 mice each, 1-way ANOVA, Tukey’s post hoc test. (N) Hepatic TAG normalized to total protein in the indicated genotypes in the mice fed with HCD; n > 6 mice each, 1-way ANOVA, Tukey’s post hoc test. (O) Quantification of CD68-positive and F4/80-positive area in the designated genotypes by ImageJ; n > 5 mice each, 1-way ANOVA, Tukey’s post hoc test. Scale bars: 150 μm. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001.