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Reducing hepatic PKD activity lowers circulating VLDL cholesterol

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journal contribution
posted on 2020-09-01, 00:00 authored by Amanda J Genders, Timothy ConnorTimothy Connor, Shona MorrisonShona Morrison, Simon T Bond, Brian G Drew, Peter J Meikle, Kirsten HowlettKirsten Howlett, Sean McgeeSean Mcgee
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.

History

Journal

Journal of Endocrinology

Volume

246

Issue

3

Pagination

265 - 276

Publisher

BioScientifica

Location

Bristol, Eng.

ISSN

0022-0795

eISSN

1479-6805

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

2020, Society for Endocrinology