Creasy Kate Townsend, Mehta Minal B, Schneider Carolin V, Park Joseph, Zhang David, Shewale Swapnil V, Millar John S, Vujkovic Marijana, Hand Nicholas J, Titchenell Paul M, Baur Joseph A, Rader Daniel J
Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.
Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sci Adv. 2025 May 16;11(20):eado3440. doi: 10.1126/sciadv.ado3440.
The gene, encoding PPP1R3B protein, is critical for liver glycogen synthesis and maintaining blood glucose levels. Genetic variants affecting expression are associated with several metabolic traits and liver disease, but the precise mechanisms are not fully understood. We studied the effects of both overexpression and deletion in mice and cell models and found that both changes in expression result in dysregulated metabolism and liver damage, with overexpression increasing liver glycogen stores, while deletion resulted in higher liver lipid accumulation. These patterns were confirmed in humans where variants increasing expression had lower liver fat and decreased plasma lipids, whereas putative loss-of-function variants were associated with increased liver fat and elevated plasma lipids. These findings support that PPP1R3B is a crucial regulator of hepatic metabolism beyond glycogen synthesis and that genetic variants affecting expression levels influence if hepatic energy is stored as glycogen or triglycerides.
编码PPP1R3B蛋白的基因对肝脏糖原合成和维持血糖水平至关重要。影响其表达的基因变异与多种代谢特征和肝脏疾病相关，但具体机制尚未完全明确。我们在小鼠和细胞模型中研究了过表达和缺失的影响，发现表达的这两种变化都会导致代谢失调和肝脏损伤，过表达会增加肝脏糖原储备，而缺失则会导致肝脏脂质积累增加。在人类中也证实了这些模式，即增加该基因表达的变异会降低肝脏脂肪并降低血浆脂质，而推定的功能丧失变异则与肝脏脂肪增加和血浆脂质升高有关。这些发现支持PPP1R3B是肝脏代谢的关键调节因子，其作用超出了糖原合成，并且影响该基因表达水平的基因变异会影响肝脏能量是以糖原还是甘油三酯的形式储存。
