用乙酰辅酶A羧化酶抑制剂(ACCi)治疗非酒精性脂肪性肝炎(NASH)可能会增加血浆甘油三酯(TG),载脂蛋白B(apoB)浓度的变化。ACC在从头脂肪生成中具有限速作用,并调节脂肪酸氧化,使其成为NASH中一个有吸引力的治疗靶点。我们的目标是确定ACCi的效果,Firsocostat,NASH中血浆低密度脂蛋白(LDL)apoB的产生率以及非诺贝特联合治疗的影响。用重水进行代谢标记和LDL-apoB富集的串联质谱分析在16例NASH患者中进行,这些患者接受了Firsocostat治疗12周,而i29NASH受试者接受了Firsocostat和非诺贝特治疗12周。在Firsocostat的NASH中,血浆TG从基线到第12周显着增加了17%(p=0.0056)。LDL-apoB替代率(FRR)也显着增加(基线至第12周:31±20.2至46±22.6%/天,p=0.03)和绝对合成率(ASR)(30.4至45.2mg/dL/天,p=0.016),但不是血浆apoB浓度.firsocostat对LDL-apoBASR的影响仅限于肝硬化患者(基线为21.0±9.6,第12周为44.2±17mg/dL/天,p=0.002,n=8);非肝硬化患者没有变化(39.8±20.8和46.3±14.8mg/dL/天,分别,p=0.51,n=8)。非诺贝特和fisocostat联合治疗可防止血浆TG升高,LDL-apoBFRR和ASR。总之,在患有肝硬化的NASH中,ACCi治疗可增加LDL-apoB100的产生速率,同时非诺贝特治疗可防止这种作用。
Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4-45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.