Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.
Int J Mol Sci. 2023 Feb 21;24(5):4315. doi: 10.3390/ijms24054315.
Glucokinase-maturity onset diabetes of the young (GCK-MODY) is a kind of rare diabetes with low incidence of vascular complications caused by gene inactivation. This study aimed to investigate the effects of GCK inactivation on hepatic lipid metabolism and inflammation, providing evidence for the cardioprotective mechanism in GCK-MODY. We enrolled GCK-MODY, type 1 and 2 diabetes patients to analyze their lipid profiles, and found that GCK-MODY individuals exhibited cardioprotective lipid profile with lower triacylglycerol and elevated HDL-c. To further explore the effects of GCK inactivation on hepatic lipid metabolism, GCK knockdown HepG2 and AML-12 cell models were established, and in vitro studies showed that GCK knockdown alleviated lipid accumulation and decreased the expression of inflammation-related genes under fatty acid treatment. Lipidomic analysis indicated that the partial inhibition of GCK altered the levels of several lipid species with decreased saturated fatty acids and glycerolipids including triacylglycerol and diacylglycerol, and increased phosphatidylcholine in HepG2 cells. The hepatic lipid metabolism altered by GCK inactivation was regulated by the enzymes involved in de novo lipogenesis, lipolysis, fatty acid β-oxidation and the Kennedy pathway. Finally, we concluded that partial inactivation of GCK exhibited beneficial effects in hepatic lipid metabolism and inflammation, which potentially underlies the protective lipid profile and low cardiovascular risks in GCK-MODY patients.
葡萄糖激酶-青少年发病型糖尿病（GCK-MODY）是一种罕见的糖尿病，由于基因失活导致血管并发症的发病率较低。本研究旨在探讨 GCK 失活对肝脂质代谢和炎症的影响，为 GCK-MODY 的心脏保护机制提供证据。我们招募了 GCK-MODY、1 型和 2 型糖尿病患者来分析他们的脂质谱，发现 GCK-MODY 个体表现出保护性的脂质谱，甘油三酯较低，HDL-c 升高。为了进一步探讨 GCK 失活对肝脂质代谢的影响，我们建立了 GCK 敲低 HepG2 和 AML-12 细胞模型，体外研究表明，在脂肪酸处理下，GCK 敲低可减轻脂质积累并降低炎症相关基因的表达。脂质组学分析表明，GCK 的部分抑制改变了几种脂质的水平，包括甘油三酯和二酰甘油在内的饱和脂肪酸和甘油酯减少，HepG2 细胞中的磷脂酰胆碱增加。GCK 失活引起的肝脂质代谢改变受从头合成、脂肪分解、脂肪酸β-氧化和 Kennedy 途径中涉及的酶调节。最后，我们得出结论，GCK 的部分失活对肝脂质代谢和炎症具有有益作用，这可能是 GCK-MODY 患者保护性脂质谱和低心血管风险的基础。
