Hyaluronan (HA) is a linear glycosaminoglycan (GAG) of extracellular matrix (ECM) synthesized by three hyaluronan synthases (HASes) at the plasma membrane using uridine diphosphate (UDP)-glucuronic acid (UDP-GlcUA) and UDP-N-acetylglucosamine (UDP-GlcNAc) as substrates. The production of HA is mainly regulated by hyaluronan synthase 2 (HAS2), that can be controlled at different levels, from epigenetics to transcriptional and post-translational modifications. HA biosynthesis is an energy-consuming process and, along with HA catabolism, is strongly connected to the maintenance of metabolic homeostasis. The cytoplasmic pool of UDP-sugars is critical for HA synthesis. UDP-GlcNAc is an important nutrient sensor and serves as donor substrate for the O-GlcNAcylation of many cytosolic proteins, including HAS2. This post-translational modification stabilizes HAS2 in the membrane and increases HA production. Conversely, HAS2 can be phosphorylated by AMP activated protein kinase (AMPK), a master metabolic regulator activated by low ATP/AMP ratios, which inhibits HA secretion. Similarly, HAS2 expression and the deposition of HA within the pericellular coat are inhibited by sirtuin 1 (SIRT1), another important energetic sensor, confirming the tight connection between nutrients availability and HA metabolism.

透明质酸 (HA) 是细胞外基质 (ECM) 的线性糖胺聚糖 (GAG)，由质膜上的三种透明质酸合酶 (HAS) 使用尿苷二磷酸 (UDP)-葡萄糖醛酸 (UDP-GlcUA) 和 UDP-N-乙酰氨基葡萄糖合成。 UDP-GlcNAc) 作为底物。HA 的产生主要由乙酰透明质酸合酶 2 (HAS2) 调节，可以在从表观遗传学到转录和翻译后修饰的不同水平上进行控制。HA 生物合成是一个消耗能量的过程，与 HA 分解代谢一起与代谢稳态的维持密切相关。UDP-糖的细胞质池对于 HA 合成至关重要。UDP-GlcNAc 是一种重要的营养传感器，可作为许多胞浆蛋白（包括 HAS2） O -GlcNAc酰化的供体底物。这种翻译后修饰可稳定膜中的 HAS2 并增加 HA 产量。相反，HAS2 可以被 AMP 激活蛋白激酶 (AMPK) 磷酸化，AMPK 是一种由低 ATP/AMP 比率激活的主要代谢调节因子，可抑制 HA 分泌。同样，HAS2 的表达和 HA 在细胞周皮内的沉积受到另一种重要的能量传感器 Sirtuin 1 (SIRT1) 的抑制，证实了营养物质可用性和 HA 代谢之间的紧密联系。