TY  - JOUR
A1  - Mayer, Alexander E.
A1  - Löffler, Mona C.
A1  - Loza Valdés, Angel E.
A1  - Schmitz, Werner
A1  - El-Merahbi, Rabih
A1  - Trujillo-Viera, Jonathan
A1  - Erk, Manuela
A1  - Zhang, Thianzhou
A1  - Braun, Ursula
A1  - Heikenwalder, Mathias
A1  - Leitges, Michael
A1  - Schulze, Almut
A1  - Sumara, Grzegorz
T1  - The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling
JF  - Science Signaling
N2  - 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 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.
KW  - Protein kinase D3 (PKD3)
KW  - cholesterol
KW  - diacylglycerol (DAG)
KW  - liver
KW  - metabolism
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250025
ET  - accepted manuscript
ER  - 
TY  - JOUR
A1  - Trujillo‐Viera, Jonathan
A1  - El‐Merahbi, Rabih
A1  - Schmidt, Vanessa
A1  - Karwen, Till
A1  - Loza‐Valdes, Angel
A1  - Strohmeyer, Akim
A1  - Reuter, Saskia
A1  - Noh, Minhee
A1  - Wit, Magdalena
A1  - Hawro, Izabela
A1  - Mocek, Sabine
A1  - Fey, Christina
A1  - Mayer, Alexander E.
A1  - Löffler, Mona C.
A1  - Wilhelmi, Ilka
A1  - Metzger, Marco
A1  - Ishikawa, Eri
A1  - Yamasaki, Sho
A1  - Rau, Monika
A1  - Geier, Andreas
A1  - Hankir, Mohammed
A1  - Seyfried, Florian
A1  - Klingenspor, Martin
A1  - Sumara, Grzegorz
T1  - Protein Kinase D2 drives chylomicron‐mediated lipid transport in the intestine and promotes obesity
JF  - EMBO Molecular Medicine
N2  - Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.
KW  - chylomicron
KW  - fat absorption
KW  - intestine
KW  - obesity
KW  - protein kinase D2/PKD2/PRKD2
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239018
VL  - 13
IS  - 5
ER  -