Reducing hepatic PKD activity lowers circulating VLDL cholesterol

Genders, Amanda J., Connor, Timothy, Morrison, Shona, Bond, Simon T., Drew, Brian G., Meikle, Peter J., Howlett, Kirsten F. and Mcgee, Sean L. 2020, Reducing hepatic PKD activity lowers circulating VLDL cholesterol, Journal of Endocrinology, vol. 246, no. 3, pp. 265-276, doi: 10.1530/JOE-19-0548.

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Title Reducing hepatic PKD activity lowers circulating VLDL cholesterol
Author(s) Genders, Amanda J.
Connor, Timothy
Morrison, Shona
Bond, Simon T.
Drew, Brian G.
Meikle, Peter J.
Howlett, Kirsten F.ORCID iD for Howlett, Kirsten F. orcid.org/0000-0002-8571-4867
Mcgee, Sean L.ORCID iD for Mcgee, Sean L. orcid.org/0000-0001-6953-106X
Journal name Journal of Endocrinology
Volume number 246
Issue number 3
Start page 265
End page 276
Total pages 12
Publisher BioScientifica
Place of publication Bristol, Eng.
Publication date 2020-09-01
ISSN 0022-0795
1479-6805
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
glucose metabolism
signal transduction
liver
gene regulation
cholesterol
PROTEIN-KINASE-D
FATTY-ACID OXIDATION
TRANSPORT CARRIERS
GLUCOSE
PHOSPHORYLATION
BINDING
GLUCONEOGENESIS
DIACYLGLYCEROL
MAINTENANCE
DISRUPTION
Summary Protein kinase D (PKD) is emerging as an important kinase regulating energy balance and glucose metabolism; however, whether hepatic PKD activity can be targeted to regulate these processes is currently unclear. In this study, hepatic PKD activity was reduced using adeno-associated virus vectors to express a dominant-negative (DN) version of PKD1, which impairs the action of all three PKD isoforms. In chow-fed mice, hepatic DN PKD expression increased whole-body glucose oxidation, but had only mild effects on glucose and insulin tolerance and no effects on glucose homeostasis following fasting and refeeding. However, circulating VLDL cholesterol was reduced under these conditions and was associated with hepatic fatty acid accumulation, but not lipids involved in lipoprotein synthesis. The limited effects on glucose homeostasis in DN PKD mice was despite reduced expression of gluconeogenic genes under both fasted and refed conditions, and enhanced pyruvate tolerance. The requirement for PKD for gluconeogenic capacity was supported by in vitro studies in cultured FAO hepatoma cells expressing DN PKD, which produced less glucose under basal conditions. Although these pathways are increased in obesity, the expression of DN PKD in the liver of mice fed a high-fat diet had no impact on glucose tolerance, insulin action, pyruvate tolerance or plasma VLDL. Together, these data suggest that PKD signalling in the liver regulates metabolic pathways involved in substrate redistribution under conditions of normal nutrient availability, but not under conditions of overnutrition such as in obesity.
Language eng
DOI 10.1530/JOE-19-0548
Indigenous content off
Field of Research 0702 Animal Production
0707 Veterinary Sciences
1103 Clinical Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2020, Society for Endocrinology
Persistent URL http://hdl.handle.net/10536/DRO/DU:30141760

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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