Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity

Jonathan Trujillo-Viera; Rabih El-Merahbi; Vanessa Schmidt; Till Karwen; Angel Loza-Valdes; Akim Strohmeyer; Saskia Reuter; Minhee Noh; Magdalena Wit; Izabela Hawro; Sabine Mocek; Christina Fey; Alexander E. Mayer; Mona C. Löffler; Ilka Wilhelmi; Marco Metzger; Eri Ishikawa; Sho Yamasaki; Monika Rau; Andreas Geier; Mohammed Hankir; Florian Seyfried; Martin Klingenspor; Grzegorz Sumara

doi:10.15252/emmm.202013548

Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity

Jonathan Trujillo-Viera
, Rabih El-Merahbi
, Vanessa Schmidt
, Till Karwen
, Angel Loza-Valdes
, Akim Strohmeyer
, Saskia Reuter
, Minhee Noh
, Magdalena Wit
, Izabela Hawro
, Sabine Mocek
, Christina Fey
, Alexander E. Mayer
, Mona C. Löffler
, Ilka Wilhelmi
, Marco Metzger
, Eri Ishikawa
, Sho Yamasaki
, Monika Rau
, Andreas Geier

Mohammed Hankir, Florian Seyfried, Martin Klingenspor, Grzegorz Sumara^*

^*Kontaktforfatter

Rudolf-Virchow-Center/DFG-Research Center for Experimental Biomedicine
University of Würzburg
Nencki Institute of Experimental Biology of the Polish Academy of Sciences
Technical University of Munich
Translational Center Regenerative Therapies (TLC-RT)
German Institute of Human Nutrition
German Center for Diabetes Research
Osaka University
University Hospital Würzburg

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	e13548
Tidsskrift	EMBO Molecular Medicine
Vol/bind	13
Udgave nummer	5
ISSN	1757-4676
DOI	https://doi.org/10.15252/emmm.202013548
Status	Udgivet - 7. maj 2021
Udgivet eksternt	Ja

Bibliografisk note

Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license

Finansiering

We thank Dr. Annette Schuermann for help with experimental procedures and for the critical reading of the manuscript. We thank Prof. Dr. C. Stigloher, Claudia Gehrig-Höhn, and the Imaging Core Facility of Biocenter of the University of Würzburg for help with the electron microscopy experiments. We are grateful to Caroline Ziegler, PD Dr. Klaus Neuhaus, and Dr. Ilias Lagkouvardos from the ZIEL Core Facility Microbiome/NGS at the Technical University of Munich for the outstanding technical assistance with sample processing for high-throughput 16S rRNA gene amplicon sequencing and for the help with statistical analysis. Dr. Olga Sumara and Dr. Izabela Sumara for comments on the manuscript. This study was funded by European Research Council (ERC) Starting Grant SicMetabol (no. 678119), Emmy Noether Grant Su 820/1-1 from the German Research Foundation (DFG), EMBO Installation Grant from European Molecular Biology Organization (EMBO), the Dioscuri Centre of Scientific Excellence—The program initiated by the Max Planck Society (MPG), managed jointly with the National Science Centre, and mutually funded by the Ministry of Science and Higher Education (MNiSW) and the German Federal Ministry of Education and Research (BMBF), and Collaborative Research Centre 1371 (CRC) Microbiome Signatures—Functional Relevance in the Digestive Tract funded by the German Research Foundation (DFG). We would like to thank Servier Medical Art by Servier (smart.servier.com) for sharing free images under a Creative Commons Attribution 3.0 Unported License. Some elements from smart.servier.com were used for creating the figures. Open Access funding enabled and organized by ProjektDEAL. We thank Dr. Annette Schuermann for help with experimental procedures and for the critical reading of the manuscript. We thank Prof. Dr. C. Stigloher, Claudia Gehrig‐Höhn, and the Imaging Core Facility of Biocenter of the University of Würzburg for help with the electron microscopy experiments. We are grateful to Caroline Ziegler, PD Dr. Klaus Neuhaus, and Dr. Ilias Lagkouvardos from the ZIEL Core Facility Microbiome/NGS at the Technical University of Munich for the outstanding technical assistance with sample processing for high‐throughput 16S rRNA gene amplicon sequencing and for the help with statistical analysis. Dr. Olga Sumara and Dr. Izabela Sumara for comments on the manuscript. This study was funded by European Research Council (ERC) Starting Grant SicMetabol (no. 678119), Emmy Noether Grant Su 820/1‐1 from the German Research Foundation (DFG), EMBO Installation Grant from European Molecular Biology Organization (EMBO), the Dioscuri Centre of Scientific Excellence—The program initiated by the Max Planck Society (MPG), managed jointly with the National Science Centre, and mutually funded by the Ministry of Science and Higher Education (MNiSW) and the German Federal Ministry of Education and Research (BMBF), and Collaborative Research Centre 1371 (CRC) Microbiome Signatures—Functional Relevance in the Digestive Tract funded by the German Research Foundation (DFG). We would like to thank Servier Medical Art by Servier ( smart.servier.com ) for sharing free images under a Creative Commons Attribution 3.0 Unported License. Some elements from smart.servier.com were used for creating the figures. Open Access funding enabled and organized by ProjektDEAL.

Dokumenter og links

10.15252/emmm.202013548

SDU link

Tjek adgangen til materialet i Syddansk Universitetsbiblioteks søgemaskine

Citationsformater

Trujillo-Viera, J., El-Merahbi, R., Schmidt, V., Karwen, T., Loza-Valdes, A., Strohmeyer, A., Reuter, S., Noh, M., Wit, M., Hawro, I., Mocek, S., Fey, C., Mayer, A. E., Löffler, M. C., Wilhelmi, I., Metzger, M., Ishikawa, E., Yamasaki, S., Rau, M., ... Sumara, G. (2021). Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity. EMBO Molecular Medicine, 13(5), Artikel e13548. https://doi.org/10.15252/emmm.202013548

@article{1498d11b99db434f99bdc9da6b9a7840,

title = "Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity",

abstract = "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.",

keywords = "chylomicron, fat absorption, intestine, obesity, protein kinase D2/PKD2/PRKD2",

author = "Jonathan Trujillo-Viera and Rabih El-Merahbi and Vanessa Schmidt and Till Karwen and Angel Loza-Valdes and Akim Strohmeyer and Saskia Reuter and Minhee Noh and Magdalena Wit and Izabela Hawro and Sabine Mocek and Christina Fey and Mayer, \{Alexander E.\} and L{\"o}ffler, \{Mona C.\} and Ilka Wilhelmi and Marco Metzger and Eri Ishikawa and Sho Yamasaki and Monika Rau and Andreas Geier and Mohammed Hankir and Florian Seyfried and Martin Klingenspor and Grzegorz Sumara",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2021",

month = may,

day = "7",

doi = "10.15252/emmm.202013548",

language = "English",

volume = "13",

journal = "EMBO Molecular Medicine",

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Trujillo-Viera, J, El-Merahbi, R, Schmidt, V, Karwen, T, Loza-Valdes, A, Strohmeyer, A, Reuter, S, Noh, M, Wit, M, Hawro, I, Mocek, S, Fey, C, Mayer, AE, Löffler, MC, Wilhelmi, I, Metzger, M, Ishikawa, E, Yamasaki, S, Rau, M, Geier, A, Hankir, M, Seyfried, F, Klingenspor, M & Sumara, G 2021, 'Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity', EMBO Molecular Medicine, bind 13, nr. 5, e13548. https://doi.org/10.15252/emmm.202013548

TY - JOUR

T1 - Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity

AU - Trujillo-Viera, Jonathan

AU - El-Merahbi, Rabih

AU - Schmidt, Vanessa

AU - Karwen, Till

AU - Loza-Valdes, Angel

AU - Strohmeyer, Akim

AU - Reuter, Saskia

AU - Noh, Minhee

AU - Wit, Magdalena

AU - Hawro, Izabela

AU - Mocek, Sabine

AU - Fey, Christina

AU - Mayer, Alexander E.

AU - Löffler, Mona C.

AU - Wilhelmi, Ilka

AU - Metzger, Marco

AU - Ishikawa, Eri

AU - Yamasaki, Sho

AU - Rau, Monika

AU - Geier, Andreas

AU - Hankir, Mohammed

AU - Seyfried, Florian

AU - Klingenspor, Martin

AU - Sumara, Grzegorz

PY - 2021/5/7

Y1 - 2021/5/7

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.

AB - 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

U2 - 10.15252/emmm.202013548

DO - 10.15252/emmm.202013548

M3 - Journal article

C2 - 33949105

AN - SCOPUS:85105086969

SN - 1757-4676

VL - 13

JO - EMBO Molecular Medicine

JF - EMBO Molecular Medicine

IS - 5

M1 - e13548

ER -

Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity

Abstract

Bibliografisk note

Finansiering

Dokumenter og links

SDU link

Fingeraftryk

Citationsformater