Reducing hepatic PKD activity lowers circulating VLDL cholesterol

Amanda J. Genders, Timothy Connor, Shona Morrison, Simon T. Bond, Brian G. Drew, Peter J. Meikle, Kirsten F. Howlett, Sean L. McGee

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)265-276
Number of pages12
JournalJournal of Endocrinology
Volume246
Issue number3
DOIs
Publication statusPublished - Sep 2020
Externally publishedYes

Keywords

  • Glucose metabolism signal transduction liver gene regulation cholesterol

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