Role of hepatic PKCβ in nutritional regulation of hepatic glycogen synthesis
Yaoling Shu, Faizule Hassan, Michael C. Ostrowski, Kamal D. Mehta
Yaoling Shu, Faizule Hassan, Michael C. Ostrowski, Kamal D. Mehta
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Research Article Hepatology

Role of hepatic PKCβ in nutritional regulation of hepatic glycogen synthesis

Abstract

The signaling mechanisms by which dietary fat and cholesterol signals regulate central pathways of glucose homeostasis are not completely understood. By using a hepatocyte-specific PKCβ-deficient (PKCβHep–/–) mouse model, we demonstrated the role of hepatic PKCβ in slowing disposal of glucose overload by suppressing glycogenesis and increasing hepatic glucose output. PKCβHep–/– mice exhibited lower plasma glucose under the fed condition, modestly improved systemic glucose tolerance and mildly suppressed gluconeogenesis, increased hepatic glycogen accumulation and synthesis due to elevated glucokinase expression and activated glycogen synthase (GS), and suppressed glucose-6-phosphatase expression compared with controls. These events were independent of hepatic AKT/GSK-3α/β signaling and were accompanied by increased HNF-4α transactivation, reduced FoxO1 protein abundance, and elevated expression of GS targeting protein phosphatase 1 regulatory subunit 3C in the PKCβHep–/– liver compared with controls. The above data strongly imply that hepatic PKCβ deficiency causes hypoglycemia postprandially by promoting glucose phosphorylation via upregulating glucokinase and subsequently redirecting more glucose-6-phosphate to glycogen via activating GS. In summary, hepatic PKCβ has a unique and essential ability to induce a coordinated response that negatively affects glycogenesis at multiple levels under physiological postprandial conditions, thereby integrating nutritional fat intake with dysregulation of glucose homeostasis.

Authors

Yaoling Shu, Faizule Hassan, Michael C. Ostrowski, Kamal D. Mehta

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Figure 6

Proposed mechanisms by which hepatic PKCβ deficiency induces hepatic glycogen synthesis upon glucose overload, and the impact of PKCβ deficiency on transcription factors implicated in differential regulation of GK and G6Pase genes.

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Proposed mechanisms by which hepatic PKCβ deficiency induces hepatic gly...
Our results link PKCβ with glycogen synthesis and extend our understanding of the underlying PKCβ-dependent transcriptional mechanisms for differential regulation of hepatic GK and G6Pase genes. (A) PKCβ deficiency enhances conversion of glucose to glycogen after glucose exposure by coordinating induction of GK expression and suppression of G6Pase expression, in combination with simultaneous dephosphorylation/activation of GS. These changes result in elevated GK/G6Pase ratio and intracellular G6P levels and promote glycogen synthesis and storage. In line with this model, GK has been suggested to have a close functional and regulatory association with glycogen synthesis through GS. PKCβ deficiency also induces expression of GK-binding protein PFK2/FBP2, a major allosteric regulator of its activity. Since G6Pase catalyzes the last step of gluconeogenesis, PKCβ deficiency can slightly reduce gluconeogenesis at the same time. The proposed mechanism has the potential to link diet-sensitive signaling kinase PKCβ with control of glycogenesis. (B) A model summarizing the orchestrated role of PKCβ in the differential regulation of hepatic GK and G6Pase genes in vivo. In this model, PKCβ contributes to the regulation of these genes through suppressing HNF-4α transactivation and enhancing FoxO1 protein stability. Thus, PKCβ deficiency enhances the ability of HNF-4α to transactivate and reduces the displacement of HNF-4α by FoxO1 from GK promoter, thereby resulting in induction of the GK promoter. At the same time, FoxO1 has also been reported to activate G6Pase expression through its synergistic interaction with HNF-4α; therefore, reduction of FoxO1 can also lead to decreased expression of the G6Pase gene. Up and down arrows indicate an increase or decrease, respectively, in protein level or activity in the liver.