Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia.
FASEB J. 2021 Dec;35(12):e22046. doi: 10.1096/fj.202101186R.
Hexosaminidase A (HexA), a heterodimer consisting of HEXA and HEXB, converts the ganglioside sphingolipid GM2 to GM3 by removing a terminal N-acetyl-d-galactosamine. HexA enzyme deficiency in humans leads to GM2 accumulation in cells, particularly in neurons, and is associated with neurodegeneration. While HexA and sphingolipid metabolism have been extensively investigated in the context of neuronal lipid metabolism, little is known about the metabolic impact of HexA and ganglioside degradation in other tissues. Here, we focussed on the role of HexA in the liver, which is a major regulator of systemic lipid metabolism. We find that hepatic Hexa expression is induced by lipid availability and increased in the presence of hepatic steatosis, which is associated with increased hepatic GM3 content. To assess the impact of HEXA on hepatic lipid metabolism, we used an adeno-associated virus to overexpress HEXA in the livers of high-fat diet fed mice. HEXA overexpression was associated with increased hepatic GM3 content and increased expression of enzymes involved in the degradation of glycated sphingolipids, ultimately driving sphingomyelin accumulation in the liver. In addition, HEXA overexpression led to substantial proteome remodeling in cell surface lipid rafts, which was associated with increased VLDL processing and secretion, hypertriglyceridemia and ectopic lipid accumulation in peripheral tissues. This study established an important role of HEXA in modulating hepatic sphingolipid and lipoprotein metabolism.
己糖胺酶 A（HexA）是一种由 HEXA 和 HEXB 组成的异二聚体，通过去除末端 N-乙酰-d-半乳糖胺将神经节苷脂鞘脂 GM2 转化为 GM3。人类的 HexA 酶缺乏会导致 GM2 在细胞中积累，特别是在神经元中，并且与神经退行性变有关。虽然 HexA 和鞘脂代谢在神经元脂质代谢的背景下已经得到了广泛的研究，但对于 HexA 和神经节苷脂降解在其他组织中的代谢影响知之甚少。在这里，我们专注于 HexA 在肝脏中的作用，肝脏是全身脂质代谢的主要调节剂。我们发现，肝脏中 Hexa 的表达受脂质可用性的诱导，并在存在肝脂肪变性时增加，这与肝 GM3 含量的增加有关。为了评估 HEXA 对肝脂质代谢的影响，我们使用腺相关病毒在高脂肪饮食喂养的小鼠肝脏中过表达 HEXA。HEXA 的过表达与肝 GM3 含量的增加以及参与糖化鞘脂降解的酶的表达增加有关，最终导致肝中鞘磷脂的积累。此外，HEXA 的过表达导致细胞表面脂筏中的蛋白质组发生重大重塑，这与 VLDL 加工和分泌增加、高甘油三酯血症和外周组织异位脂质积累有关。这项研究确立了 HEXA 在调节肝鞘脂和脂蛋白代谢中的重要作用。
