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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.

SUBMITTER: Trujillo-Viera J

PROVIDER: S-EPMC8103097 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Trujillo-Viera Jonathan J El-Merahbi Rabih R Schmidt Vanessa V Karwen Till T Loza-Valdes Angel A Strohmeyer Akim A Reuter Saskia S Noh Minhee M Wit Magdalena M Hawro Izabela I Mocek Sabine S Fey Christina C Mayer Alexander E AE Löffler Mona C MC Wilhelmi Ilka I Metzger Marco M Ishikawa Eri E Yamasaki Sho S Rau Monika M Geier Andreas A Hankir Mohammed M Seyfried Florian F Klingenspor Martin M Sumara Grzegorz G

EMBO molecular medicine 20210505 5

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 acti ...[more]

PMID: 33949105

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Project description:Background & aimsThere are no studies investigating the direct effects of elevated xanthine oxidase (XO) on lipid metabolism disorders. Here, we aimed to clarify the role of XO in lipid metabolism in a prospective cohort study and elucidate the underlying mechanisms.MethodsThe association between serum XO activity and metabolic associated steatotic liver disease (MASLD) was examined in Cox proportional hazard models in a population-based cohort of 3,358 participants (20-75 years) at baseline. In addition, mouse models were used to investigate the underlying mechanism for the association between overexpression of XO and the lipid metabolism disorders.ResultsAfter an average 5.8 years of follow up, we found elevated serum XO activity was associated with an increased risk of developing MASLD (hazard ratio [HR]: 2.08; 95% CI: 1.44-3.01; p-trend <0.001). Moreover, serum XO activity was significantly associated with serum triglyceride levels (r = 0.68, p <0.001). We demonstrated that hepatic XO expression increased in liver samples from patients with MASLD. Using tissue-specific Xdh knockin mice, we observed rapid lipid metabolism disorders under a high-fat diet rather than a normal chow diet. We found that XO overexpression promotes the absorption of excess dietary fat in the small intestine. Inhibition of XO also significantly reduced the absorption of fat in mice fed a high-fat diet.ConclusionsOur study clarified the association between serum XO activity levels and the development of MASLD in a large population-based prospective cohort study. Furthermore, our mouse models demonstrated that XO overexpression promotes lipid accumulation through mechanisms involving excessive fat absorption by the small intestine.Impact and implicationsUsing a prospective population-based cohort and various animal models, we have identified novel mechanisms by which xanthine oxidase regulates lipid metabolism. Our findings indicate that xanthine oxidase overexpression promotes lipid accumulation by increasing the absorption of excess dietary fat and possibly facilitating lipid transport in vivo. These results could be important for the development of therapies to treat diseases associated with lipid metabolism disorders.

Dataset Information

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

Publications

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

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