Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
Laboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Cell Mol Gastroenterol Hepatol. 2021;12(3):1001-1019. doi: 10.1016/j.jcmgh.2021.04.013. Epub 2021 May 7.
BACKGROUND & AIMS: Pharmacologic agents targeting bile acid signaling show promise for treating nonalcoholic steatohepatitis (NASH). However, clinical findings suggest that new treatment strategies with enhanced therapeutic efficacy and minimized undesired effects are needed. This preclinical study investigates whether combining an apical sodium-bile acid transporter (ASBT) inhibitor GSK233072 (GSK672) and fibroblast growth factor-15 (FGF15) signaling activation improves anti-NASH efficacy.
Mice with high fat, cholesterol, and fructose (HFCFr) diet-induced NASH and stage 2 fibrosis are used as a NASH model. GSK672 or AAV8-TBG-FGF15 interventions are administered alone or in combination to HFCFr diet-fed mice.
The combined treatment significantly enhances therapeutic efficacy against steatosis, inflammation, ballooning, and fibrosis than either single treatment. Mechanistically, the synergistic actions of GSK672 and FGF15 on inhibiting gut bile acid reuptake and hepatic bile acid synthesis achieve greater magnitude of bile acid pool reduction that not only decreases bile acid burden in NASH livers but also limits intestinal lipid absorption, which, together with FGF15 signaling activation, produces weight loss, reduction of adipose inflammation, and attenuated hepatocellular organelle stress. Furthermore, the combined treatment attenuates increased fecal bile acid excretion and repressed bile acid synthesis, which underlie diarrhea and hypercholesterolemia associated with ASBT inhibition and FGF19 analogue, respectively, in clinical settings.
Concomitant ASBT inhibition and FGF15 signaling activation produce metabolic changes that partially mimic the bariatric surgery condition whereby lipid malabsorption and increased FGF15/19 signaling synergistically mediate weight loss and metabolic improvement. Further clinical studies may be warranted to investigate whether combining ASBT inhibitor and FGF19 analogue enhances anti-NASH efficacy and reduced treatment-associated adverse events in humans.
靶向胆汁酸信号的药物在治疗非酒精性脂肪性肝炎（NASH）方面显示出前景。然而，临床研究结果表明，需要新的治疗策略，以提高治疗效果，减少不良作用。本临床前研究旨在探讨联合应用顶端钠-胆汁酸转运体（ASBT）抑制剂 GSK233072（GSK672）和成纤维细胞生长因子 15（FGF15）信号激活是否能提高抗 NASH 疗效。
采用高脂肪、胆固醇和果糖（HFCFr）饮食诱导的 NASH 和 2 期纤维化小鼠作为 NASH 模型。GSK672 或 AAV8-TBG-FGF15 干预单独或联合应用于 HFCFr 饮食喂养的小鼠。
联合治疗对脂肪变性、炎症、气球样变和纤维化的治疗效果明显优于单一治疗。机制上，GSK672 和 FGF15 联合抑制肠道胆汁酸重吸收和肝脏胆汁酸合成的协同作用，使胆汁酸池的减少幅度更大，不仅降低了 NASH 肝脏中的胆汁酸负担，而且限制了肠道脂质吸收，与 FGF15 信号激活一起，导致体重减轻、脂肪炎症减少和肝细胞细胞器应激减轻。此外，联合治疗可减少粪便胆汁酸排泄增加和胆汁酸合成抑制，这分别与临床 ASBT 抑制和 FGF19 类似物相关的腹泻和高胆固醇血症有关。
同时抑制 ASBT 和激活 FGF15 信号会产生代谢变化，部分模拟减肥手术条件，其中脂质吸收不良和 FGF15/19 信号协同介导体重减轻和代谢改善。可能需要进一步的临床研究来探讨联合应用 ASBT 抑制剂和 FGF19 类似物是否能提高抗 NASH 疗效，并减少人类治疗相关的不良反应。
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