Dyrk1b Displaces Fkbp12 from mTORC2, Causes its Activation and Triggers De Novo Lipogenesis: Implications for the Treatment of Diet-Induced Fatty Liver Disease

Abstract

The mechanisms that unify the association of insulin-induced de novo lipogenesis (DNL) with hepatic insulin resistance in metabolic syndrome (MetS) are not understood. We had previously shown that rare mutations in the DYRK1B gene are associated with MetS. We now demonstrate that Dyrk1b is a missing link between DNL and hepatic insulin resistance. The increased levels of liver Dyrk1b promoted, while its disruption conferred protection against enhanced glucose production, liver insulin-resistance and steatosis in mice. Mechanistically, Dyrk1b facilitated insulin-induced DNL in a kinase-independent manner by displacing Fkbp12 from mTORC2, causing its activation. Accordingly, the disruption of the hepatic mTORC2 rescued Dyrk1b induced hepatic steatosis and hyperlipidemia. The significance of this disease pathway is further illustrated by increased hepatic Dyrk1b levels in mice and humans with hepatic steatosis. These findings identify Dyrk1b and Fkbp12 as regulators of DNL in the setting of hepatic insulin resistance and attractive therapeutic targets against metabolic syndrome.

Keywords: Dyrk1b, NAFLD, DNL, mTORC2, Fkbp12