Gankyrin-deficiency reprograms intrahepatic glucose and lipid metabolism to delay liver regeneration

Abstract

Liver regeneration is a critical adaptive response to hepatic injury, requiring precise metabolic reprogramming to meet the energetic and biosynthetic demands of proliferating hepatocytes. While the oncoprotein Gankyrin is well-established as a promoter of liver fibrosis and hepatocarcinogenesis, its role in metabolic adaptations underlying liver regeneration remains unclear. In this study, we demonstrate that Gankyrin deficiency in the liver (Gank△Hep/Y) induces hepatic hypertrophy and aberrant glycogen accumulation. Gankyrin expression is significantly upregulated after partial hepatectomy (PHx), whereas Gank△Hep/Y -PHx mice exhibit impaired liver regeneration. This impairment is marked by a delayed restoration of the liver-to-body weight ratio, blunted glycogenolysis, and reduced fatty acid uptake. Mechanistically, Gankyrin activates Pygl and Cd36, key regulators of glycogenolysis and lipid uptake, respectively. Pharmacological inhibition of PYGL activity retards liver regeneration. Furthermore, we identify a novel interaction between Gankyrin and FOXO1, wherein Gankyrin promotes FOXO1 ubiquitination and subsequent proteasomal degradation. This Gankyrin-dependent suppression of FOXO1 leads to the transcriptional upregulation of Pygl and Cd36, thereby fueling hepatocyte proliferation. Collectively, our findings reveal Gankyrin as a master regulator of liver regeneration, integrating metabolic reprogramming with proliferative signaling through the FOXO1-PYGL/CD36 axis. These insights not only elucidate the mechanistic underpinnings of liver regeneration but also unveil the therapeutic potential of targeting the Gankyrin/FOXO1 pathway to mitigate hepatic insufficiency and enhance regenerative capacity in clinical settings.

1. Introduction

Liver is a central metabolic hub, endowed with extraordinary regenerative potential that enables it to recover from injury and maintain homeostasis [1,2]. Under physiological conditions, the liver exhibits a remarkable regeneration capacity, restoring its mass and function following damage [3,4]. However, this regeneration capacity is severely compromised in clinical scenarios involving extensive liver resections, acute liver failure, severe chronic liver injury or hepatocellular carcinoma [5‒8]. Despite decades of research, effective strategies to accelerate liver regeneration remain elusive. Thus, understanding the mechanisms of liver regeneration is critical for the design of innovative interventions to restore hepatic function in patients with severe liver injury or disease.

The 70% partial hepatectomy (PHx) model is the most common paradigm for investigating the mechanism underlying liver regeneration [9,10]. In response to regeneration signals, a series of metabolic adaptations occur in the liver and system-wide, fundamentally altering the metabolic landscape [11]. During the early phase of liver regeneration, rapid glycogen depletion leads to transient hypoglycemia, a hallmark of the initial regenerative response [12,13]. However, compensatory mechanisms are activated, including enhanced gluconeogenesis and suppressed glycolysis [14]. Notably, interfering with this hypoglycemic response, such as exogenous glucose supplementation, can negatively affect hepatocyte proliferation [15]. In response to glucose depletion, the regenerating liver shifts its primary energy source from glucose to fatty acid β-oxidation, resulting in transient hepatic steatosis [16,17]. This lipid accumulation is driven by increased fatty acid uptake from adipose tissue [18,19]. The accumulation of lipid droplets significantly influences subsequent liver regeneration. Intriguingly, de novo hepatic lipogenesis is dispensable for resection-induced steatosis [20]. Understanding these metabolic adjustments could provide insights into therapeutic strategies to enhance liver regeneration.