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.
Highlights
The liver plays an important role in maintaining plasma glucose homeostasis by adjusting a delicate balance between hepatic glucose utilization and production, derangements of which occur in metabolic diseases [1, 2]
To define the physiological and molecular consequences of depleted hepatic Protein kinase C β (PKCβ) signaling on glucose homeostasis, we generated PKCβHep–/– mice depleted of PKCβ in hepatic cells by crossing floxed PKCβ mice (PKCβfl/fl) with albumin-Cre mice [16]
The pyruvate tolerance test (PTT), which measures the rate of de novo glucose synthesis, showed that inactivation of hepatic PKCβ improved tolerance to exogenous pyruvate injection in PKCβHep–/– mice relative to controls, suggesting that hepatic gluconeogenesis may be decreased in the absence of PKCβ (Figure 1F)
Summary
The liver plays an important role in maintaining plasma glucose homeostasis by adjusting a delicate balance between hepatic glucose utilization and production, derangements of which occur in metabolic diseases [1, 2]. The liver adapts to feeding through several events, including suppressing gluconeogenesis and upregulating glycogen synthesis, which result in a net switch from hepatic glucose output to hepatic glucose uptake. These adaptive responses are critical for maintaining glucose homeostasis in response to glucose overload. GK is considered to play an essential role in sensing and maintaining proper blood glucose levels in response to a rising level of glucose This kinase mediates hepatic glucose uptake, and its product glucose-6-phosphate (G6P) is a central metabolite for intrahepatic glucose homeostasis. Well-coordinated hepatic glucose metabolism is essential to health, and dysregulation of hepatic glucose metabolism is central to the pathogenesis and complications of type 2 diabetes mellitus
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