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.
View: Text | PDF
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

×

Figure 4

Dyrk1b promotes DNL in the liver.

Options: View larger image (or click on image) Download as PowerPoint
Dyrk1b promotes DNL in the liver. (A) Graph showing the absolute amount ...
(A) Graph showing the absolute amount of deuterium-labeled (M+1 and M+2) palmitate to unlabeled palmitate quantified by gas chromatography–mass spectrometry in the indicated genotypes. The contribution of naturally occurring M+1 and M+2 palmitates was subtracted. Percent enrichment × TAG (mg/g): AAVcontrol, 19.55 ± 1.18, n = 9; Dyrk1bAAV-WT, 37.55 ± 2.75, n = 8; Dyrk1bAAV-kin.def, 38.19 ± 5.79, n = 5; 1-way ANOVA, Tukey’s post hoc test. (B and C) Expression and quantification of designated proteins in the liver of the indicated mice fed with CD, after 6-hour fast; n = 4 mice each genotype, unpaired t test, 2-sided. (D and E) Expression and quantification of designated proteins in the liver of the indicated mice fed with HCD after 6-hour fast; n = 4 mice each genotype, unpaired t test, 2-sided. (F and G) Rate of hepatic triglyceride secretion (F) and incremental area under the curve (iAUC) (G) upon i.p. administration of weight-normalized poloxamer-407 (P-407) in the designated mice on CD for 3 months. iAUC values were calculated by subtraction of baseline (0 minutes) values from other time points, to minimize the bias from high plasma TAG at baseline in Dyrk1bAAV-WT mice. The mice were fasted for 6 hours and plasma collected at the indicated times after P-407 injection. AAVcontrol, 126.9 mg/dL/h; Dyrk1bAAV-WT, 136.9 mg/dL/h; n > 5 each group, unpaired t test, 2-sided. (H and I) Rate of hepatic triglyceride secretion (H) and iAUC (I) upon administration of P-407 in the designated mice on HCD for 3 months; scrambledAAV, 448.1 mg/dL/h; Dyrk1bAAV-shRNA, 377.2 mg/dL/h; n = 5 each genotype, unpaired t test, 2-sided. *P ≤ 0.05, **P ≤ 0.01.