Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Endocrinol (Lausanne). 2023 Aug 29;14:1247611. doi: 10.3389/fendo.2023.1247611. eCollection 2023.
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.
非酒精性脂肪性肝病（NAFLD）是一种全球性的常见肝脏疾病，受遗传和环境因素的共同影响。2 型糖尿病（T2D）是一种独立的环境风险因素，可引发肝脂肪变性，并加速其向严重肝损伤阶段进展。此外，T2D 和 NAFLD 的共存会协同增加心血管疾病的风险。然而，NAFLD 中遗传易感性与代谢风险因素之间的关联仍不完全清楚。葡萄糖激酶调节基因（）负责编码葡萄糖激酶调节蛋白（GKRP），在肝脏中作为葡萄糖代谢酶葡萄糖激酶（GK）的调节剂和保护剂。基因内的两个常见变体（rs1260326 和 rs780094）与较低的 T2D 风险和较高的 NAFLD 风险相关。最近的研究强调，T2D 的存在显著放大了基因的作用，从而增加了 NAFLD 患者发生 NASH 和纤维化的风险。在这篇综述中，我们重点关注 GKRP 在 T2D 和 NAFLD 中的关键作用，借鉴遗传和生物学研究的见解。值得注意的是，先前使用葡萄糖激酶激活剂（GKAs）靶向 GK 的药物开发尝试显示出增加血浆甘油三酯或 NAFLD 的潜在风险。相反，在糖尿病大鼠中过度表达 GKRP 改善了葡萄糖耐量而不会导致 NAFLD，这表明 GKRP 在维持肝脏葡萄糖和脂质代谢平衡方面具有关键的调节作用。总的来说，这篇综述揭示了基因与环境在 NAFLD 中的复杂相互作用，重点关注基因。通过整合遗传学、生物学和药物开发的证据，我们重新评估了针对 GK 或 GKRP 治疗代谢性疾病的治疗潜力。新出现的证据表明，选择性激活 GK 或增强 GK-GKRP 结合可能代表一种恢复葡萄糖和脂质代谢平衡的整体策略。
