Genetic and pharmacological targeting of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. We report that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator activated receptor-alpha (PPARα) transcription and fatty acid β-oxidation (FAO), and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, blocking oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lower steatosis, inflammation, and fibrosis by inducing PPARα-driven FAO, and suppressing monocyte chemotaxis, nuclear factor-kappaB and transforming growth factor-beta targets. These findings highlight hepatic oxalate overproduction as a new target for the treatment of MASH. The genome-wide analysis of DNA methylation in CpG islands through unbiased reduced representation bisulfite sequencing (RRBS) between control and MASH condition in either chow diet or MASH diet fed mice for 24 weeks.

代谢功能障碍相关性脂肪性肝炎（Metabolic dysfunction-associated steatohepatitis, MASH）的发病率呈上升趋势，且现有药物治疗手段有限，亟需鉴定新型代谢靶点。草酸盐是乳酸脱氢酶（LDHA）代谢乙醛酸产生的终末代谢产物；肝特异性丙氨酸-乙醛酸转氨酶（AGXT）可对乙醛酸进行解毒，从而阻止草酸盐蓄积。本研究发现，在MASH患者与小鼠的肝脏中，AGXT表达受抑且LDHA活性上调，进而导致草酸盐过量生成。反之，草酸盐可通过抑制过氧化物酶体增殖物激活受体α（PPARα）的转录与脂肪酸β氧化（FAO）过程，促进肝细胞脂肪变性，并通过C-C基序趋化因子配体2诱导单核细胞趋化。在饮食诱导MASH的雄性小鼠中，通过肝特异性AGXT过表达或药物抑制LDHA以阻断草酸盐过量生成，可通过激活PPARα介导的脂肪酸β氧化、抑制单核细胞趋化及核因子κB与转化生长因子β的靶基因通路，有效减轻脂肪变性、炎症与纤维化。上述研究结果表明，肝脏草酸盐过量生成可作为MASH治疗的新型靶点。本研究通过无偏好性简化代表性亚硫酸氢盐测序（RRBS）技术，对喂食正常饲料或MASH造模饲料、造模24周的对照组与MASH模型组小鼠的CpG岛区域开展全基因组DNA甲基化分析。