Protein Kinase D2 drives chylomicron‐mediated lipid transport in the intestine and promotes obesity. Issue 5 (5th May 2021)

• Record Type: Journal Article
• Authors: Trujillo‐Viera, Jonathan; El‐Merahbi, Rabih; Schmidt, Vanessa; Karwen, Till; Loza‐Valdes, Angel; Strohmeyer, Akim; Reuter, Saskia; Noh, Minhee; Wit, Magdalena; Hawro, Izabela; Mocek, Sabine; Fey, Christina; Mayer, Alexander E; Löffler, Mona C; Wilhelmi, Ilka; Metzger, Marco; Ishikawa, Eri; Yamasaki, Sho; Rau, Monika; Geier, Andreas; Hankir, Mohammed; Seyfried, Florian; Klingenspor, Martin; Sumara, Grzegorz
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 5(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-05
• Subjects: chylomicron -- fat absorption -- intestine -- obesity -- protein kinase D2/PKD2/PRKD2; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202013548
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: We show that upon fat ingestion, Protein Kinase D2 stimulates chylomicron‐mediated triglyceride absorption in the intestine. Targeting PKD2, genetically or with small molecule inhibitors, reduces triglycerides absorption and prevents the development of obesity in mice and presumably in humans. PKD2 enhances chylomicron size and therefore chylomicron‐mediated triglycerides absorption. PKD2 phosphorylates chylomicron‐associated lipoprotein, APOA4. Inhibition of PKD2 diminishes obesity and associated diabetes. PKD2 activity correlates with triglycerides levels in obese patients. Abstract : We show that upon fat ingestion, Protein Kinase D2 stimulates chylomicron‐mediated triglyceride absorption in the intestine. Targeting PKD2, genetically or with small molecule inhibitors, reduces triglycerides absorption and prevents the development of obesity in mice and presumably in humans.