Luo Yi, Decato Benjamin E, Charles Edgar D, Shevell Diane E, McNaney Colleen, Shipkova Petia, Apfel Abraham, Tirucherai Giridhar S, Sanyal Arun J
Bristol Myers Squibb, Princeton, NJ, USA.
Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, VA, USA.
JHEP Rep. 2021 Nov 12;4(1):100392. doi: 10.1016/j.jhepr.2021.100392. eCollection 2022 Jan.
BACKGROUND & AIMS: Increased serum bile acids (BAs) have been observed in patients with non-alcoholic steatohepatitis (NASH). Pegbelfermin (PGBF), a polyethylene glycol-modified (PEGylated) analogue of human fibroblast growth factor 21 (FGF21), significantly decreased hepatic steatosis and improved fibrosis biomarkers and metabolic parameters in patients with NASH in a phase IIa trial. This exploratory analysis evaluated the effect of PGBF on serum BAs and explored potential underlying mechanisms.
Serum BAs and 7α-hydroxy-4-cholesten-3-one (C4) were measured by HPLC-mass spectrometry (MS) using serum collected in studies of patients with NASH (NCT02413372) and in overweight/obese adults (NCT03198182) who received PGBF. Stool samples were collected in NCT03198182 to evaluate faecal BAs by liquid chromatography (LC)-MS and the faecal microbiome by metagenetic and metatranscriptomic analyses.
Significant reductions from baseline in serum concentrations of the secondary BA, deoxycholic acid (DCA), and conjugates, were observed with PGBF, but not placebo, in patients with NASH; primary BA concentrations did not significantly change in any arm. Similar effects of PGBF on BAs were observed in overweight/obese adults, allowing for an evaluation of the effects of PGBF on the faecal microbiome and BAs. Faecal transcriptomic analysis showed that the relative abundance of the gene encoding choloylglycine hydrolase, a critical enzyme for secondary BA synthesis, was reduced after PGBF, but not placebo, administration. Furthermore, a trend of reduction in faecal secondary BAs was observed.
PGBF selectively reduced serum concentrations of DCA and conjugates in patients with NASH and in healthy overweight/obese adults. Reduced choloylglycine hydrolase gene expression and decreased faecal secondary BA levels suggest a potential role for PGBF in modulating secondary BA synthesis by gut microbiome. The clinical significance of DCA reduction post-PGBF treatment warrants further investigation.
Pegbelfermin (PGBF) is a hormone that is currently being studied in clinical trials for the treatment of non-alcoholic fatty liver disease. In this study, we show that PGBF treatment can reduce bile acids that have previously been shown to have toxic effects on the liver. Additional studies to understand how PGBF regulates bile acids may provide additional information about its potential use as a treatment for fatty liver.
在非酒精性脂肪性肝炎（NASH）患者中观察到血清胆汁酸（BA）升高。聚乙二醇化人成纤维细胞生长因子21（FGF21）类似物佩格贝弗明（PGBF）在一项IIa期试验中显著降低了NASH患者的肝脂肪变性，并改善了纤维化生物标志物和代谢参数。这项探索性分析评估了PGBF对血清BA的影响，并探讨了潜在的作用机制。
使用在NASH患者（NCT02413372）和接受PGBF的超重/肥胖成年人（NCT03198182）研究中收集的血清，通过高效液相色谱-质谱联用（HPLC-MS）测定血清BA和7α-羟基-4-胆甾烯-3-酮（C4）。在NCT03198182中收集粪便样本，通过液相色谱（LC）-MS评估粪便BA，并通过宏基因组和宏转录组分析评估粪便微生物群。
在NASH患者中，观察到PGBF组的次级胆汁酸脱氧胆酸（DCA）及其共轭物的血清浓度较基线显著降低，而安慰剂组未出现此现象；任何一组中初级胆汁酸浓度均无显著变化。在超重/肥胖成年人中也观察到PGBF对胆汁酸有类似作用，这使得能够评估PGBF对粪便微生物群和胆汁酸的影响。粪便转录组分析显示，编码次级胆汁酸合成关键酶胆酰甘氨酸水解酶的基因相对丰度在给予PGBF后降低，而给予安慰剂后未降低。此外，还观察到粪便次级胆汁酸有降低趋势。
PGBF选择性降低了NASH患者以及健康超重/肥胖成年人血清中DCA及其共轭物的浓度。胆酰甘氨酸水解酶基因表达降低和粪便次级胆汁酸水平降低表明PGBF在调节肠道微生物群次级胆汁酸合成中可能发挥作用。PGBF治疗后DCA降低的临床意义值得进一步研究。
佩格贝弗明（PGBF）是一种目前正在临床试验中用于治疗非酒精性脂肪性肝病的激素。在本研究中，我们表明PGBF治疗可降低先前已证明对肝脏有毒性作用的胆汁酸。进一步了解PGBF如何调节胆汁酸的研究可能会提供有关其作为脂肪肝治疗药物潜在用途的更多信息。
