The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling

Please always quote using this URN: urn:nbn:de:bvb:20-opus-250025
  • Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletionHepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.show moreshow less
Metadaten
Author: Alexander E. MayerORCiD, Mona C. LöfflerORCiD, Angel E. Loza ValdésORCiD, Werner SchmitzORCiD, Rabih El-MerahbiORCiD, Jonathan Trujillo-VieraORCiD, Manuela Erk, Thianzhou Zhang, Ursula Braun, Mathias Heikenwalder, Michael Leitges, Almut SchulzeORCiD, Grzegorz SumaraORCiD
URN:urn:nbn:de:bvb:20-opus-250025
Document Type:Journal article
Faculties:Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Fakultät für Biologie / Rudolf-Virchow-Zentrum
Language:English
Parent Title (English):Science Signaling
Year of Completion:2019
Edition:accepted manuscript
Source:Science Signaling 12, 593 (2019). DOI: 10.1126/scisignal.aav9150
DOI:https://doi.org/10.1126/scisignal.aav9150
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31387939
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 572 Biochemie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:Protein kinase D3 (PKD3); cholesterol; diacylglycerol (DAG); liver; metabolism
Release Date:2021/12/02
EU-Project number / Contract (GA) number:678119
OpenAIRE:OpenAIRE
Licence (German):License LogoDeutsches Urheberrecht