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 10

Dyrk1b increases membrane DAG and impairs insulin receptor activation.

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Dyrk1b increases membrane DAG and impairs insulin receptor activation. (...
(A and B) Glucose (A) and insulin (B) during intraperitoneal glucose tolerance test (IPGTT) in Dyrk1bAAV-WT mice after 6-hour fast; n > 8 mice per group, 1-way ANOVA, Holm-Šidák post hoc test, P (area under the curve) = 0.0025. (C and D) Insulin tolerance test (ITT) on Dyrk1bAAV-WT (C) and Dyrk1bAAV-shRNA mice (D). After 6 hours of fasting, fast-acting Humulin (0.75 U/kg) was injected i.p., and glucose was measured at indicated time points. n > 8 mice per group, 1-way ANOVA, Holm-Šidák post hoc test. (E and F) Liver glycogen quantification in the indicated mice after fast/refeed for 6 hours; n > 13 mice each group for E, n > 9 for F, unpaired t test, 2-sided. (G) Plasma membrane sn-1,2-, sn-1,3-, and sn-2,3-DAG levels in Dyrk1bAAV-WT mice; n > 6 mice each group, unpaired t test, 2-sided. (H) Membrane PKCε levels after fractionation into membrane and cytosolic fractions; n > 6 mice each group, unpaired t test, 2-sided. (I) p-IRKT1150 enrichment by immunoprecipitation in liver lysates of the indicated mice; n > 4 mice each group, unpaired t test, 2-sided. (J and K) p-IRKY1162 in liver samples from Dyrk1bAAV-WT mice only fasted (J) or fasted and stimulated with insulin for 15 minutes (K); n > 3 mice each group, unpaired t test, 2-sided. (L) Plasma membrane sn-1,2-, sn-1,3-, and sn-2,3-DAG levels in Dyrk1bAAV-shRNA mice; n > 6 mice each, unpaired t test, 2-sided. (M) p-IRKT1150 enrichment by immunoprecipitation in the indicated liver lysates; n > 4 mice each group, unpaired t test, 2-sided. (N and O) p-IRKY1162 in liver samples from fasted (N, n = 3 mice each group) and insulin-stimulated (O, n > 5 mice each group) Dyrk1bAAV-shRNA mice; unpaired t test, 2-sided. *P ≤ 0.05, **P ≤ 0.01.