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.

A phosphoproteomic approach reveals that PKD3 controls PKA-mediated glucose and tyrosine metabolism

“…Protein kinase D (PKD) family members integrate multiple hormonal and metabolic signals to coordinate homeostasis of the organism ( Sumara et al, 2009 ; Rozengurt, 2011 ; Löffler et al, 2018 ; Mayer et al, 2019 ; Kolczynska et al, 2020 ; Trujillo-Viera et al, 2021 ). The family of PKDs comprises three kinases: PKD1, PKD2, and PKD3 ( Fu & Rubin, 2011 ; Rozengurt, 2011 ).…”

“…PKD1 and PKD2 share the highest homology, whereas PKD3 kinase is the unique member of the family. PKD1 and PKD2 have been widely studied in different cellular processes such as trans-Golgi network dynamics, cell proliferation, and cell migration, adipocytes and enterocyte function, insulin secretion as well as regulation of innate and adaptive immune cells function ( Sumara et al, 2009 ; Rozengurt, 2011 ; Gehart et al, 2012 ; Ittner et al, 2012 ; Goginashvili et al, 2015 ; Zhang et al, 2017 ; Löffler et al, 2018 ; Mayer et al, 2019 ; Kolczynska et al, 2020 ; Trujillo-Viera et al, 2021 ). PKD3 has been implicated in tumor progression and invasiveness in breast and gastric cancers, as well as hepatocellular carcinoma ( Huck et al, 2014 ; Yang et al, 2017 ; Zhang et al, 2019 ).…”

When fat meets the gut—focus on intestinal lipid handling in metabolic health and disease

“…In line with this idea, a recent study showed that the lack of protein kinase D2 (PKD2) in mice results in increased circulating levels of APOA4 but decreased lipid absorption and body weight gain in association with a healthier metabolic profile in these mice and enrichment of the microbiota with anti‐obesogenic members of Bacteroides spp. in the intestine (Trujillo‐Viera et al , 2021). Since no difference was found in the amount of APOB48 (reflecting the abundance of CM), and PKD2 directly phosphorylates APOA4, the lack of this post‐translational modification might be responsible for the observed phenotype (Trujillo‐Viera et al , 2021).…”

“…in the intestine (Trujillo‐Viera et al , 2021). Since no difference was found in the amount of APOB48 (reflecting the abundance of CM), and PKD2 directly phosphorylates APOA4, the lack of this post‐translational modification might be responsible for the observed phenotype (Trujillo‐Viera et al , 2021). Hypothetically, PKD2‐dependent phosphorylation of APOA4 might promote maturation/lipidation of the CM by increasing the retention time in the ER.…”

“…The use of a small‐molecule inhibitor of PKD2 as well as PKD1 and PKD3 (CRT0066101), also allowed a localized inhibition of this pathway in the small intestine, thereby decreasing intestinal lipid absorption to ameliorate obesity and restore insulin sensitivity. Notably, activity of PKD2 in the small intestine of obese patients was found to correlate with plasma TG levels (Trujillo‐Viera et al , 2021). These results demonstrate that regulation of abundance and enzymatic modifications of APOA4 might be of therapeutic use for the treatment of obesity and hyperlipidemia.…”